Below are the topics of all the sections in the Special Update Edition. Just click on any of the topics and this will take you to the beginning of that section.
Nine Years at a Glance
AFSA has officially reached
the million dollar mark in contributions! We have provided a steady
supply of seed money for new and experienced investigators for nine
years. Twenty-three projects have been funded and we are making a
substantial impact on research progress in the field of fibromyalgia
syndrome (FMS) and overlapping conditions such as chronic fatigue
syndrome (CFS). It takes tremendous effort to recruit applicants who
have a strong sense of what is patient-relevant, and who have the
skills to accomplish the proposed project, but this is only one facet
of our job.
While our primary focus
is to fund research on FMS/CFS, our responsibilities to our donors
extend beyond the distribution of award monies. Not only do we feel
compelled to describe the details of each project funded, but AFSA
is, and will continue to be, accountable for explaining the progress
and results of previously funded studies. This is an implied promise
to you, our contributor, that AFSA will follow through on every award
made ... not just to the point of each project's completion, but also
beyond. As you read through this Special Update Edition, you will
learn how many of the investigators who have been funded by AFSA are
thriving in this field of study. They have become the mentors of a
new generation of researchers interested in helping you.
FMS afflicts millions of
people, but an elite group of roughly 3,500 people (mostly patients)
have fueled the success of AFSA in recent years. As one of AFSA's
donors, we want you to feel an immense sense of accomplishment. The
many milestones that AFSA has achieved are all due to your generosity.
Our volunteer staff, along with our donors and funded researchers,
work as a larger, more empowered team to advance the scientific understanding
The existing treatments
for FMS/CFS leave much to be desired, but as you read this Update,
please note that the projects funded by AFSA are opening up new avenues
of thinking, with the next step being the investigation of novel therapeutic
approaches. Although most of these new pharmacological concepts will
require additional seed money, we hope that you will find them worth
pursuing so that someday soon you will truly feel better.
Naturally, you are entitled
to ask: Why doesn't the pharmaceutical industry or NIH foot the bill
for new interventions for FMS? This is a great question! Over the
years, I have discovered that most drug companies don't have FMS in
mind for their new products, although there is some glimmer of hope
in this area. The drug companies will require more research data to
convince them that investing in FMS treatment trials will payoff.
As for NIH, many researchers have informed me that the "drug
treatment" section of their grant proposals were axed. This is
because the NIH expects pharmaceutical companies to pick up the tab,
rather than the taxpayers. There are also substances naturally produced
by the body that can't be patented, and therefore, no one wants to
take the first step in developing them for FMS. For example, a substance
produced in the brain called gamma hydroxybutyrate (GHB), enhances
slow-wave sleep, doubles growth hormone secretion during the night
in healthy humans, and blocks activation of the pain amplifying NMDA
receptors. These are all great properties for a potential drug to
treat FMS, but GHB is a regulated drug. Until more research is conducted
on this substance, it will not be prescribed to FMS patients. If this
situation weren't bad enough, the NIH has recently decided to cut
back on its FMS/CFS awards so that it can allocate more funds to what
they consider more "worthy" diseases, such as AIDS and cancer.
The information contained
in this special edition is fresh and reported for the first time.
With AFSA being the only charity that funds research
on your illness, we understand that this places a hefty burden on
you. Rest assured that you will be the first to learn about new breakthroughs
funded by AFSA. As a donor, your opinions about how contibutions should
be spent are welcome. It is my sincere hope that nine years from now
I will be writing to you about highly effective treatments for FMS/CFS,
and that AFSA will no longer be reliant upon your support!
Best wishes to all.
Founder and President
[Back to Table of Contents]
Objective Tests to Validate Your Pain
be able to effectively measure the pain of FMS in order to determine
the impact of exercise or other therapeutic interventions. This may
seem like an obvious concept and goal, but its implementation in FMS
has always been a challenge. At the October 2002 American College
of Rheumatology (ACR) meeting, AFSA-funded researcher Roland Staud,
M.D., explained that one of the primary interests of his research
team at the University of Florida in Gainesville is to be able to
explain the pain of FMS. He estimates that tender points account for
roughly 9% of an FMS patient's pain at any given time. In fact, most
patients meet all 18 of the prerequisite tender points, so there is
a ceiling effect when using tender points as a measure of pain. They
are helpful for diagnostic purposes and they validate that a person
has widespread pain, but they really don't provide an accurate measure
of a person's pain level.
At the American Pain Society
meeting in March of 2003, Staud presented a protocol for measuring
pain that enables him to determine 49% of a fibromyalgia patient's
pain at any given time.1 This is by far much better than
the 9% afforded by tender point scores! An important ingredient of
the protocol involves the measurement of "second pain" or
what is commonly called windup.
To fully understand the
implications of Staud's previous work in assessing the impact of exercise,
as well as his more recently published studies that evaluate medications,
it is essential to understand windup. In fact, measurements of windup
and similar objective pain tests are rapidly becoming the gold standard
in FMS research. Gone are the days when study participants are simply
checked for tender points and asked to rate their pain from one to
ten ... so it is essential that you understand the new way of doing
research. Instead of getting weighed down by the intricacies of neuroscience,
just imagine yourself in the driver's seat at a busy intersection.
There are two main types
of fibers in your body that transmit information to your brain about
a painful stimulus in your peripheral tissues. You have your high-speed
"carpool express lanes" that are A-delta fibers carrying
information to your brain instantaneously about a particular stimulus.
These fibers help you react quickly to potential dangers, such as
withdrawing your hand from a hot surface. You also have fibers that
transmit signals at much slower velocities (like cars in slow moving
school zones), roughly one-tenth the speed, and they are called C-fibers.
These fibers are thought to be more important in the process of windup
and chronic pain states such as FMS. If you apply a heat stimulus
to the hand, a person can actually feel the arrival of the two inputs
to their central nervous system. It may take a bit of training on
the part of the technician and the patient, but first pain (A-delta
fiber inputs) can be distinguished from second pain (C-fiber inputs).
"The mechanisms that
lead to chronic pain are clearly related to spinal cord mechanisms,"
says Staud. Indeed, another AFSA-funded researcher, Serge Marchand,
Ph.D., of the University of Sherbrooke in Canada, has uncovered
a defect in the diffuse noxious inhibitory control (DNIC) system that
is designed to tone down pain at the spinal cord level. Staud and
Marchand use different pain test procedures, but their conclusions
converge: the spinal cord mechanisms in FMS patients don't work well.
The spinal cord is where
the NMDA receptors and the wide dynamic range neurons reside. When
the NMDA receptors are activated by incoming signals, they have the
capability of amplifying pain. Also, if the pain lingers (like cars
at a traffic accident), the wide dynamic range neurons can pick up
the signal and transmit it to regions nearby in the spinal cord. It
is similar to the situation when a traffic accident occurs on a southbound
highway and the northbound travelers slow down to take a look at what
is going on. Lanes traveling both north and south become congested
and even the side roads become backed up with traffic. While this
is an oversimplification of what happens when the NMDA receptors and
the wide dynamic range neurons become involved, it forms a basis to
explain how regional pain can lead to body-wide central pain. And
once this widespread pain syndrome gets going, it has the ability
to cause changes in the way the body processes pain (in this analogy,
drivers avoid the highway altogether and begin taking the side roads).
So far, scientists have not figured out how to undo these unwanted
changes in the spinal cord that work to perpetuate the pain.
Although the above processes
explain how the spinal cord can amplify pain (as symbolized by the
traffic congestion and the sprawling detour routes), there are opposing
mechanisms at the level of the spinal cord to minimize your pain.
Noxious inputs can turn on the production of endogenous (internally
produced) opioids to tone down the impact of the signal. This can
also cause the release of noradrenaline, serotonin, GABA, or endorphins
(natural intrinsic morphine) into the spinal region to reduce the
sensation of pain. The problem that Staud alludes to in FMS is that
the pain-amplifying or pain-facilitating systems in the spinal cord
may be overpowering the pain-relieving mechanisms, and this can lead
to a situation of central pain, more specifically, FMS and increased
Using the analogy of cars,
highways, 2-way and 4-way stop signs, yield signs, green lights, and
side streets, the windup concept is illustrated in the Car Analogy
Diagram (the PDF file of the diagram can be downloaded below). As
the slow velocity C-fiber inputs arrive at the spinal cord, they may
pile up like a traffic jam and lead to an added pain effect. Of course,
in healthy humans, this pile up of pain would be promptly relieved
by the body's production of opioids and other pain relievers in the
spinal cord. This backlog of pain signals can be measured objectively
as windup (temporal summation) and it is the additive potential for
pain signals to cause enhanced pain. In the car analogy, this means
a greater backlog of cars on the C-fiber Highway and side streets
during a period of time because "temporal" is related to
The most wonderful aspect
about the measurements of windup (temporal summation of pain) and
DNIC activity (spatial summation of pain) is that neither are invasive
test procedures. Marchand's experiments are designed to directly measure
DNIC activity and the details of his work will be described later.
Suffice it to say, all that is needed to measure what is happening
within the spinal cord is an external extremity, such as a hand or
arm. No invasive methods, injection of dyes or expensive imaging equipment
is needed ... just well-trained technicians and roughly $7,000 worth
of equipment that is set up by researchers who know what they are
doing (e.g., Drs. Staud and Marchand).
Exercise Increases Windup in FMS Patients
In June of 1999, AFSA
funded Staud $30,000 to show that exercise increases windup in patients
with FMS, which may explain why you ache all over after too much exertion.
The project, The Effect of Graded Exercise on Temporal Summation
of Second Pain (Windup) in Patients with Fibromyalgia Syndrome,
was successfully completed and published in the peer-reviewed literature
for others to read.2
Exercise has always been
touted as something that makes people feel great, such as the "runner's
high" experienced by athletes. This is in direct opposition to
the claims by FMS patients who say that their symptoms flare after
too much exertion. So the focus of this study was to objectively assess
pain before and after exercise by using windup as an indicator of
what is happening at the level of the spinal cord. Please refer to
the diagram of the car analogy, and to the table at the end of this
section which summarizes the study and its findings.
here for the Car Analogy Diagram (PDF)
opiate and noradrenergic systems in proportion to the magnitude and
duration of the exercise," writes Staud and coworkers in his
published report on the AFSA-funded project. These endogenous pain-relieving
systems should reduce the intensity of painful sensations, and using
this logic, exercise should reduce pain sensitivity. Yet, there is
a twist to the situation. Short-term acute stress is known to trigger
the pain-relieving system, but chronic stress increases pain sensitivity
(which may be a similar situation to persistent FMS pain). So Staud's
study was designed to look at the effects of maximal exercise on pain
sensitivity in healthy pain-free control subjects and patients with
The study design directly
compared the effects of strenuous exercise on clinical pain and on
the additive effects of second pain (windup or temporal summation)
when exposed to a repetitive experimental pain stimulus. The working
hypothesis was that the endogenous inhibitory systems designed to
control pain would not be effectively mobilized by exercise in patients
with FMS. In other words, a pile up of pain signal inputs, such as
the traffic jam analogy, was expected to be measured as increased
windup in the FMS test group. In addition, it was hypothesized that
the effects of exercise in patients with FMS would cause an exacerbation
of clinical pain (how patients said they felt).
Remember, it is second
pain that arrives by the slow-velocity C-fibers; first pain is ten
times faster. With second pain arriving in such a delayed fashion,
if one undergoes a process that causes repeat stimulation (such as
exercise or repeat stimulus testing), then the spinal cord mechanisms
will not get a break from the inputs. The repeated inputs to the spinal
cord will continue to add up or build up to what is called temporal
summation or windup (again, visualize this as a pile up of cars in
heavy traffic, except here we are dealing with a pile up of C-fiber
inputs). The effects of first pain will likely vanish immediately,
so that the A-Delta fibers are not the focus of the study's measurements.
If the pain stimulus interval is at least 3 seconds apart, Staud's
group found that second pain on the "C-fiber Highway" vanishes
in healthy control subjects.3 Remember, it is first pain
that usually vanishes and second pain has the potential to linger
if the amplifying systems in the spinal cord are turned on (i.e.,
the NMDA receptors) and/or the pain-relieving systems are not activated
(i.e., release of the body's opioids and other substances) ... which
is the hypothetical case for FMS.
Providing a repetitive
pain stimulus (varying from 2 to 5 seconds apart) before and after
exercise, Staud and coworkers were able to determine the degree to
which the endogenous inhibitory mechansims pitched in to moderate
the pain produced by a 15-minute exercise program (both mild and strenuous
intensities were tested). Ratings of repetitive painful stimuli after
exercise were also measured for each group (healthy and FMS subjects)
to determine how the two groups felt between 1.5 and 10 minutes after
the exercise program.
In the healthy individuals,
the endogenous inhibitory mechanisms appear to have been activated
because exercise significantly reduced their pain when given repetitive
heat stimulus testing to their hand 1.5 minutes and 10 minutes after
exercise. The endogenous opioid effects were most apparent soon after
exercise (the post-exercise test 1.5 minutes later), but it also reduced
pain up to 10 minutes following exercise. This "feel great"
finding was more substantial after the subjects performed strenuous
exercise, but it also occurred to a lesser degree after mild exercise
(performed on a different day). This means that the endogenous pain-inhibitory
system was working well in healthy subjects to keep the traffic moving
swiftly so that pain signals didn't "pile up" to amplify
the pain. In other words, they didn't lead to problems of windup.
There was no difference
between healthy males and healthy females on the improvements in pain
threshold and no detection of windup when their hand was subjected
to a repeat heat stimulus at 3 second intervals or greater. This is
important to note because it means that this test of windup is not
influenced by gender. But when it came to FMS patients, the findings
were completely different.
Baseline testing of both
pain-free and FMS patients confirmed Staud's previous finding that
FMS patients have increased pain at rest that can be objectively measured
as windup or temporal summation. "In addition," write the
authors, "temporal summation was evident for subjects with FMS
at slower repetition rates than for pain-free subjects." This
means that the closer the interval for the painful heat stimuli, the
greater the differences detected between healthy pain-free subjects
and FMS patients.
Now, what about the results
of testing after exercise? As already mentioned, exercise in healthy
subjects caused an activation of the pain-relieving opioid system,
even for mild exercise. For the most part, the opposite effect occurred
in patients with FMS; the endogenous inhibitory system was either
not activated or it was overpowered by the pain-facilitating system
(e.g., activations of the NMDAs). Exercise caused an exacerbation
of pain in FMS patients, and more importantly, it led to increased
windup or temporal summation of pain, which can be measured objectively.
Asking Dr. Staud about
the most crucial point made by his study on exercise, he says, "The
important information from this research included the fact that exercise
does not attenuate windup (or temporal summation of pain) compared
to normal pain-free controls, but it increases windup. This finding
emphasizes abnormal pain mechanisms in FMS and may explain the increased
pain sensitivity that FMS patients experience with exercise."
The AFSA-funded pilot
study not only won an award at the 2001 American Pain Society meeting,
but also enabled Staud (along with his colleagues Charles Vierck,
Ph.D., and Donald Price, Ph.D.) to receive funding from
NIH to further his work to objectively measure windup in FMS patients
receiving dextromethorphan and fentanyl. Dextromethorphan is a weak
NMDA receptor antagonist and fentanyl is a mu-acting opioid agonist
(acts like an opioid), which is the key ingredient in the Duragesic
The findings by Staud
on these two drugs were presented at the ACR meeting in October of
2002. Preliminary work was published this year in PAIN as well
as in abstract form at the 2002 ACR and 2003 APS meetings.4,5,6 Staud found that both dextromethorphan and fentanyl (tested individually)
were each effective in reducing windup in patients with FMS. Although
the results were only obtained with one-time dosing of each drug,
the results are promising and Staud hopes to expand his studies to
longer-term treatment trials in patients with FMS.
- Temporal relates
- Summation is additive
- Measures ability
of pain-processing systems in spinal cord to handle a repetitive
stream of noxious inputs produced at timed intervals
- Windup (temporal
summation) is the additive effect of the repeat stimuli; it's
detected as an increase in pain sensation with time (as the
stimuli continue to be applied).
- Healthy individuals
do not detect any increase in pain with repeat stimuli at
3 second intervals or greater; their pain-inhibitory system
works to obliterate the pain
- If repeat stimulus
is generated at intervals less than every 3 seconds, healthy
individuals begin to experience windup (it's painful and they
tell the pain tester to stop the stimuli).
- Windup effects
are independent of genderthe response is the same for
healthy males and healthy females.
- FMS patients have
increased windup at rest (the repeat noxious stimuli, even
when spread out to every 5 seconds, becomes very painful to
- AFTER EXERCISE
(funded by AFSA)
- Healthy subjects: stimulates endogenous pain-relieving
system and produces a "feel great" effect that can
be measured as increased pain threshold
- FMS patients: The pain-inhibitory system is not adequately
activated, leading to activation of the pain-facilitating
system. Result: increased windup (more so than at rest), patients
experience enhanced pain with repeat stimulus testing.
- AFTER FENTANYL
(funded by NIH)
- Fentanyl is an opioid-like substance and the active ingredient
in the Duragesic Patch; administration reduced windup, presumably
by aiding the pain-inhibitory system.
- AFTER DEXTROMETHORPHAN
(funded by NIH)
- Dextromethorphan is an NMDA receptor antagonist; administration
reduced windup, presumably by minimizing the pain-facilitating
Diffuse Noxious Inhibitory Control (DNIC) System
... it's the pain "traffic controller" in the spinal cord
So far, we have discussed
the body's response to a repetitive painful stimulus to look at its
additive effect on a person's pain. In the pain literature this additive
effect with time (like the cars piling up) is called temporal summation
or windup. In healthy people, windup is not much of a problem because
the C-fiber signals arriving at their spinal cord activate the pain-relieving
or diffuse noxious inhibitory control (DNIC) system (opioids, noradrenaline,
etc.). The pain-facilitating or amplifying system (i.e., NMDAs) is
not activated. So healthy humans handle the signals as they arrive,
and nothing accumulates to cause problems. Yet, preliminary findings
from an AFSA-funded project indicate that the system doesn't work
like this in people with FMS. Now, in order to fully appreciate the
research by Serge Marchand, Ph.D., another AFSA-funded investigator,
it is important to grasp the concept of spatial summation.
Spatial summation of pain
is related to the amount of surface area stimulated. The greater the
surface area stimulated, the greater the pain intensity one should
feel based on pure intuition. However, the body has a DNIC system
that operates by sending inhibitory signals from higher centers in
the brain stem, down into the spinal cord and it can inhibit pain
signals or filter them out before they reach the pain-processing centers
in the brain.
How does the DNIC system
actually work? When the C-fiber signals arrive in the central nervous
system, it poors out endogenously produced opioids, noradrenaline,
serotonin, and GABA. These substance originate in the brain stem and
then work in the spinal cord. The DNIC is the pain-relieving
system already described in the previous sections on windup. Opposing
the DNIC are the pain-facilitating (or amplifying) abilities of the
NMDA receptors and wide dynamic range neurons. Of course, substances
that activate the NMDAs would also be part of this pain-facilitating
system, such as substance P, nerve growth factor, and excitatory amino
acids. The involvement of the excitatory amino acids is unclear, but
both substance P and nerve growth factor are greatly increased in
the spinal fluid of patients with FMS.
So once again, we have
the two opposing pain-inhibitory and pain-facilitory systems, but
one of the basic goals of the AFSA-funded project was to measure the
subject's response to increasing the amount of surface area exposed
to a heat stimulus. In June of 2000, AFSA awarded $49,407 to co-investigators Serge Marchand, Ph.D., and Pierre Arsenault, M.D., Ph.D.,
for a multi-faceted project entitled: The Role of DNIC in FMS Pain
and Treatment. Marchand and Arsenault were at the University of
Quebec, but have since moved to the University of Sherbrooke where
Marchand is chairman of the chair in pain neuroscience.
The first aim of the AFSA
project was to validate that DNIC function could be accurately tested
in healthy men and women, and to provide a larger comparison group
of healthy controls. This portion of the project was published in
2002.7 The second aim of the project was to test the DNIC
of people with FMS and another group of patients with low back pain
(a regional pain syndrome). This part of the study is also completed
has been presented at the IASP meeting (Julien et al., 2002).8 It is now in preparation for publication. The third aim of the study
involved a treatment trial using Effexor-ER, in which the DNIC of
FMS patients was tested before and after an eight-week trial period.
Effexor-ER increases the central nervous system levels of serotonin
and noradrenaline, although its impact on serotonin is more substantial.
This final portion of the project is now completed and it's being
written up for formal publication.9
of using a thermal tapping on the hand (as in Staud's work), Marchand's
experiments use a bath of circulating water maintained at a specified
temperature. He evaluates the effects of what happens when a person
increases the amount of their arm submerged into the bath. Remember,
that intuitively, one would expect that the greater the amount of
the arm submerged (greater surface area), the greater the person's
pain intensity rating. If you look at the generalized diagram below,
the line for the healthy controls should be a straight diagonal line,
increasing upward with increased amount of arm submerged. However,
this is not what Marchand found. In healthy people, their DNIC system
is activated to provide pain relief despite being subjected to a greater
surface area of pain stimulus.
How does the term spatial
summation come into play? It is the additive effect of pain unpleasantness
when one's arm is submerged in either a hot or cold water bath stimulus
(see diagram). If the DNIC system kicks in, as it does for healthy
individuals, there isn't much spatial summation because the pain intensity
plateaus off. The situation is different for FMS, in which the pain
intensity continues to increase as greater portions of the arm are
submerged. This causes increased spatial summation, which mathematically
is the area under the curve in the graph.
Marchand was kind enough
to share with AFSA contributors the role that his funding by AFSA
has played in his career, that of new FMS researchers working with
him, how the results should lead to a better understanding of FMS,
and generate other exciting areas of interest.
the award meant to us:
Writing grant proposals is a time-consuming task, but it is a necessary
step for pursuing a career as a researcher. So whenever a charity,
such as AFSA, awards money for a project that a researcher is interested
in performing, it has special meaning. First, it proves that a group
of people, in this case those affected by the chronic symptoms of
FMS/CFS, believe in our work. It is of special importance to us to
know that we have the support of the people that we are hoping to
help with our investigations. Second, being funded by an organization
that employs a formal grant review process consistsing of many of
the leading researchers in the field signifies to us that we are judged
to have the capacity to perform the proposed project, collect the
necessary data to seek larger sums of money from other granting institutions,
and to guarantee that the development of our understanding of FMS/CFS
proceeds with the goal of better treatments in the long run. Finally,
grants from charitable associations are treatment oriented; they provide
researchers with the ability to perform studies that will have clinical
implications (i.e., patient-relevance).
it enabled us to do:
With the grant from AFSA, we were able to collect enough data to have
results for thirteen medical conference presentations, one
paper published,7 and two papers in the preparation stage.8,9 In parallel with our AFSA-related work, we began researching the role
of sex hormones in pain, because we believe that they are related
to our interest in understanding more about the pain mechanisms involved
in patients with FMS. We recently published one paper on this topic,10 and we have several projects ongoing.11,12,13
A good measurement of the
interest of a research team for a particular topic is directly related
to the number of graduate students working on a project related to
that topic. We have one PhD student investigating the role of endogenous
pain modulation in fibromyalgia (Nancy Julien) and one PhD
student doing fundamental research in animals on the role of sex hormones
(Isabelle Gaumond). We have one more student starting his PhD
on the role of sex hormones in human pain (Itachi Falanga).
An MSc student has just joined our team to look at the differences,
as well as the similarities, between the chronic pain mechanisms involved
in fibromyalgia, low back pain, and irritable bowel syndrome (Yannick
Tousignant-Laflamme). We also have a colleague (Jacques Charest)
supervising a student (Claire Beaudry) who is obtaining her
master's degree on the role of adapted physical activity on pain in
people with FMS. As one can easily see, we are in the process of expanding
our research in the field of understanding the neurophysiological
mechanisms of fibromyalgia by enlarging our team of researchers interested
in helping individuals with FMS.
Project Results; Future Directions
summation and pain
using spatial summation as a way to objectively measure the role of
the endogenous pain modulation systems in healthy men and women has
already been published.7 We have just submitted the next
paper in which we demonstrate that FMS pain is related to a deficit
of the endogenous pain-inhibitory mechanisms (the DNIC system) while
chronic low back pain is not. These results may explain why the pain
of FMS is diffuse rather than regional in nature. A deficit of the
diffuse noxious inhibitory control (DNIC) systems can lead to heightened
pain sensitization (hyperalgesia) and pain following non-painful stimulation
(allodynia). Understanding the role of a deficitive DNIC system in
fibromyalgia as well as the impact of supplementing the neurotransmitters
involved in this system, such as serotonin (5HT), noradrenaline (NA)
and endogenous opioids (this includes such compounds as endorphins
and enkephalins - ENK ), would help in the development of more effective
treatments. In addition, our spatial summation model enables us to
test the effect that these agents have on the DNIC system in people
and similarities between
fibromyalgia, chronic low back pain, irritable bowel syndrome (IBS),
The goal of this AFSA-related project is to identify the specifics
of FMS mechanisms by studying different aspects of the neurophysiology
of pain in patient groups that share some symptoms with FMS. They
all suffer with chronic pain and/or depression to varying degrees,
and in some cases they also exhibit diffuse pain (such as FMS and
IBS). Nancy Julien, M.Sc., is completing her PhD work on this
topic and has just submitted a paper to be considered for publication.8 Yannick Tousigant-Laflamme, PT, has joined our team and will
be doing his MSc on this subject as well. Comparing the different
pathologies involved in these conditions will permit us to better
understand them and should lead to the development of specific treatments
based on mechanisms rather than solely on symptoms.
with Effexor: DNIC Function and Clinical Symptoms of FMS
The DNIC system uses endogenously produced opioids, serotonin, noradrenaline,
GABA, and other pain-fighting substances to tone down the noxious
inputs at the level of the spinal cord. Given that low serotonin and
noradrenaline levels have been reported in the spinal fluid of patients
with FMS, it makes sense to test the effectiveness of a drug that
raises the central nervous system levels of these two substances.
Effexor primarily increases serotonin (5HT), but it mildly elevates
noradrenaline (NA) levels as well.
An elaborate 9-week, blinded
and placebo controlled trial of Effexor in patients with FMS was just
completed. The cross-over design meant that all 25 FMS patients were
tested on the Effexor and the placebo (just a sugar pill in this case).
Throughout the study period at set intervals, the DNIC function (or
spatial summation) was evaluated for each patient. We are now at a
point where we have a massive amount of data to analyze. We wish to
take a careful look at who responded to the Effexor and if their response
correlated with changes in their objectively measured DNIC function,
or spatial summation. Naturally, we will be evaluating the dosage
most commonly taken by patients and the most frequent side effects
reported. Our goal is to be able to correlate as much of our data
to clinical improvements, since the primary objective of our ever-expanding
research team is to find out how to help chronic pain and FMS patients
role of sex hormones
Several arguments implicate sex hormones in pain perception and in
the development of some chronic pain conditions. Many studies demonstrate
that pain thresholds vary across the menstrual cycle in women (higher
threshold in follicular phase).14,15,16 In other words,
women experience less pain during the first half of their cycle which
is dominated by estrogen. Greater pain levels are usually experienced
in the second half of the cycle, which is dominated by progesterone.
Moreover, the onset or the remission of some chronic pain conditions
varies across lifetime; boys and girls have the same pain thresholds
and the same prevalence of pain conditions before puberty.17 Furthermore, women present an increase in pain thresholds and increased
levels of analgesia during pregnancy.18,19 Finally, it
is well established that receptors for sex hormones have a wide distribution
in the central nervous system where they can modulate the pain-transmitting
pathways and/or endogenous pain-inhibitory systems, such as DNIC.20,21,22 Isabelle Gaumond, M.Sc., of our research teams has shown that
in rats, both female and male sex hormones modulate pain perception
and that female sex hormones seem to play a pro-nociceptive (pain-facilitating)
role while male sex hormones appear to play a protective or pain-inhibitory
role.10 Isabelle Gaumond is now a PhD student and will
continue her investigation of the role of sex hormones in relation
to various structures in the brain that could be playing a pain-modulating
role. She will also employ brain imaging techniques (MRI) in her research
projects. Our new PhD student, Itachi Falanga, M.Sc., will
continue to work on the role of sex hormones as they relate to pain
The results of these projects
will help improve our understanding of the role of sex hormones and
pain, as well as the relation between sex hormones and certain neurotransmitters
implicated in fibromyalgia (5HT, NA, ENK). These results could lead
to the development of combined hormone therapy with pharmacological
treatments in FMS.
DNIC Function/Spatial Summation
- Spatial relates
to surface area
- Summation is
- Spatial summation
is the additive effect of increasing exposure to hot or cold
- Intuitively: the
greater the surface area exposed to the hot/cold temperature,
the greater the perceived pain intensity
- DNIC Influence:
As increasing surface area is exposed to painful hot/cold
water, the DNIC system minimizes pain intensity by pouring
out opioids, serotonin, noradrenaline, etc.
- Healthy individuals
(both male and females) exhibit the DNIC influence
- DNIC in healthy people similar to low back pain (regional
pain syndrome) but not FMS patients (diffuse pain syndrome), in preperation
- Impact of Effexor (serotonergic, noradrenergic drug) on
FMS pain and DNIC response, data being analyzed for publication
- The DNIC system may be more pronounced in healthy males
as opposed to females because it is likely influenced by hormones
such as testosterone.
- An animal study recently coauthored by Isabelle Gaumond,
Ph.D., indicates that testosterone may have a protective
pain effect, while female hormones, estrogen and progesterone,
exert more of a pain-facilitory effect (in other words, making
the pain worse). This may help explain the female predominance
of painful disorders. Fortunately, this study supports the
concept that the problem may not be caused by the structure
of the central nervous system, but rather, the way the hormones
influence the nervous system's response to painful stimuli.
In other words, female rats whose ovaries have been removed
can be placed on testosterone and their pain responses will
mimic those of male rats.
- Human studies using hormonal manipulation to minimize pain
are in the planning stage.
There is no question in
my mind, or that of my colleagues and students, that the AFSA grant
played a significant role in starting our research in FMS. Your support
is well appreciated, and will lead to advances in both the fundamental
and clinical research aspects of fibromyalgia.
- Staud R, Robinson M, Price DE, Vierck C: Central Sensitization Predicts Clinical Pain in Fibromyalgia. J of Pain 4(2 suppl 1):8, #667, 2003.
- Vierck CJ, Staud R, Price DD, Cannon RL, Mauderli AP, Martin AD: The effect of maximal exercise on temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. J of Pain 2(6):334-344, 2001.
- Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD: Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 91(1-2):165-175, 2001.
- Staud R, Robinson ME, Vierck CJ, Price DD: Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 101:167-174, 2003.
- Staud R, Robinson ME, Mauderli AP, Cannon RL, Vierck CJ, Price DD: Opioids modulate the enhanced temporal summation of second pain of fibromyalgia patients. Arthritis & Rheum 46(9 suppl):S396,#1027, 2002.
- Staud R, Robinson M, Mauderli A, Cannon R, Vierck C, Price D: Dextromethorphan Attenuates Thermal Wind-Up of Fibromyalgia Patients. J of Pain 4(2 suppl 1):20, #667, 2003.
- Marchand S, Arsenault P: Spatial summation for pain perception: interaction of inhibitory and excitatory mechanisms. Pain 95(3):201-206, 2002.
- Julien N, Arsenault P, Marchand S: Spatial Summation in Pain Perception: Deficits of endogenous pain inhibition in fibromyalgia but not in low-back pain. IASP, San Diego, 782-P52, 2002.
- Julien N, Arsenault P, Marchand: Overview of Fibromyalgia Treatments. American Pain Society, Phoenix, AZ, April 2001. For more details, see Web site at: www.afsafund.org.
- Gaumond I, Arsenault P, Marchand S: The role of sex hormones on formalin-induced nociceptive responses. Brain Research 958(1):139-145, 2002.
- Gaumond I, Arsenault P, Marchand S: The role of sex hormones supplementation in male and female rats on nociceptive responses. American Pain Society, Atlanta, GA, November 1-4, 2000.
- Gaumond I, Arsenault P, Jasmin P, Marchand S: The role of sex hormones in rat nociceptive responses. Society for Neuroscience Abstracts, New Orleans, LA, November 4-9, 2000.
- Gaumond I, Arsenault P, Marchand S: Stress induced analgesia: Sex hormones specificity on noradrenergic and serotoninergic brainstem neurons. IASP, San Diego, August, 2002.
- Berkley KJ: Sex differences in pain. Behav Brain Science 20(3):371-380,1997.
- Fillingim RB, Maixner W, Girdler SS, Light KC, Harris MB, Sheps DS, Mason GA: Ischemic but not thermal pain sensitivity varies across the menstrual cycle. Psychosom Med 59(5):512-520, 1997.
- Riley JL, Robinson ME, Wise EA, Price DD: A meta-analytic review of pain perception across the menstrual cycle. Pain 81(3):225-235, 1999.
- Robinson JE, Short RV: Changes in breast sensitivity at puberty, during the menstrual cycle, and at parturition. British Med Journal 1(6070):1188-1191, 1977.
- Cogan R, Spinnato JA: Pain and discomfort thresholds in late pregnancy. Pain 27(1):63-68, 1986.
- Gintzler AR: Ovarian sex steroids activated antinociceptive systems and reveal gender-specific mechanisms. Sex, Gender and Pain. Fillingim RB (Ed.). Vol. 17, pp. 89-108, Seattle, 2000.
- Aloisi AM: Sensory effects of gonadal hormones. Sex, Gender and Pain. Fillingim RB (Ed.). Vol. 17, pp. 7-24, Seattle, 2000.
- Amandusson A, Hallbeck M, Hermanson O, Blomqvist A: Estrogen-induced alterations of spinal cord enkephalin gene expression. Pain 83(2):243-248, 1999.
- Smith SS: Female sex steroid hormones: from receptors to networks to performance—actions on the sensorimotor system. Prog Neurobiol 44(1):55-86,1994.
[Back to Table of Contents]
The Neuroscience of FMS Pain (Includes Dr. Larson's Mast Cell Theory)
it be nice if every neurochemical abnormality in FMS was known and all
researchers had to do was figure out a way to fix them? We aren't to
that point yet ... but scientists are working hard to reach this goal.
At a March 2003 meeting on pain, neuroscientist Alice Larson, Ph.D.,
described a potential model for FMS. Her model, described below, takes
into account every neurochemical abnormality known in this condition,
as well as the variety of symptoms. Larson's model is complex, but for
any patient that lives and breathes with this illness, this should come
as no surprise! There is nothing easy about FMS, but it is reassuring
to read about the tenacity with which the researchers in the field are
masterminding theories and developing hypotheses that would not have
been conceivable ten years ago.
The field of neuroscience
and its relationship to FMS pain is rapidly expanding. As you read about
the studies performed by Drs. Larson, Russell, Stewart and Jasmin, you
will note that their AFSA-funded projects played an important role in
the developing theories pertaining to the neuroscience of FMS pain.
There are still many avenues to be pursued, as is evident from Larson's
speech, but progress is being made and the groundwork for effective
therapies is being constructed!
A Possible Cause of Fibromyalgia
Based on speech by Alice Larson, Ph.D., University of Minnesota Focus on Pain meeting, March 9, 2003 in Orlando, Florida
If one were to develop a research model to explain what is happening
in FMS (even if it is just on paper), it must account for many essential
factors that occur in this condition. For example, the pain is chronic,
and yet, Larson says that most of the models used by scientists for
testing pain are for acute pain scenarios. The results found by these
models can't be extrapolated to FMS. Another problem that makes developing
a model for FMS difficult: "Pain is just one component."
Elaborating on the other
components of FMS, Larson says exacerbation of symptoms by stress, as
well as triggering the onset of FMS by trauma, surgery, or infections
(all of them stressors), can make it more difficult to conceptualize
a model for FMS. The cause of the pain is always described by patients
as coming from the muscles and yet there doesn't appear to be any damage
to the muscles. Even at the characteristic tender points, there appears
to be no tissue damage. The tender points also happen to occur in areas
of the body where there is very little innervation (not many nerve fibers
in the region). "This is a big paradox," says Larson, because
one would expect that areas with lots of nerve endings should generate
more pain. "Another facet that is paradoxical about FMS is that
it is symmetrical, and that hints at the fact that it is probably centrally
mediated." Sleep disorders are also common in FMS, which again
points to the fact that this is not just a pain syndrome.
Essentials for an FMS Model:
- Serotonin and tryptophan
low in blood
- Dynorphin elevated
in spinal fluid
- Threefold increase
in spinal fluid substance P
- Fourfold increase
in spinal fluid NGF
- Widespread hyperalgesia
or enhanced pain sensitivity
- Symptoms exacerbated
- No obvious tissue
- Symmetrically located
- Sleep disorder
- High female predominance
- Symptoms influenced
by sex hormones
- Altered blood flow
to the thalamus in response to stimuli
Before describing her model,
which is basically a description of the processes that may be causing
FMS, Larson first identified a number of biochemical factors that are
already known about this condition. After all, any conceptual model
for FMS would have to account for these abnormalities. Serotonin and
its precursor, tryptophan, are low in the blood of patients with FMS.
Dynorphin, an opioid compound that alleviates pain in low concentrations
but produces pain at high concentrations, is elevated in the spinal
fluid of people with FMS.1 Several different investigators
have reported elevated levels of substance P in the spinal fluid of
individuals with FMS. Larson points to this finding as being the first
objective indication "that this is a painful disorder and not something
that is in the patient's mind." Although she talks about FMS as
being centrally mediated, she is referring to the brain structures and
certainly not the mind. "Fibromyalgia is in my mind because I am
thinking about it, but it is in the patient's brain. That's an important
Going back to substance P,
how and why is it elevated in the spinal fluid of FMS patients? "We
knew that substance P was elevated, but there was no tissue damage at
the tender points, so where was this substance P coming from?"
posed Larson. "Usually, when you have tissue damage, nerve growth
factor (NGF) is synthesized in the area of the tissue damage or trauma.
Then the NGF molecules are transported back to the cell body (located
alongside the spinal cord) and the presence of NGF causes enhanced synthesis
of substance P in the spinal fluid. But this can't be happening if there
is no obvious tissue damage in the periphery. So, our hypothesis was
that the NGF was already elevated centrally" (e.g., in the spinal
Larson's initial involvement
in FMS research centered around testing her hypothesis that NGF was
elevated in the spinal fluid of patients with this condition. She knew
from prior studies that NGF increased pain sensitivity (hyperalgesia)
and speculated that this may be the problem within the spinal fluid
of patients with FMS. Larson's published results indicated that her
hunch was correct.2 NGF in the spinal fluid of healthy control
subjects was compared to patients with "primary FMS" (no other
medical problems besides the FMS or what researchers call primary FMS).
The primary FMS patient group had a fourfold increase in NGF. But it's
known that roughly 30% of patients with lupus and rheumatoid arthritis
also have the widespread pain of fibromyalgia that tends to develop
"secondary" to or after the onset of these other autoimmune
conditions. Do these patients with "secondary FMS" also have
elevated NGF in their spinal fluid? Larson separated the two FMS patient
groups into primary and secondary FMS, and found that the NGF levels
in the "secondary" group were the same as those of the healthy
controls; they were normal. What does this tell us? "It just means
that there may be a different etiology (cause) for the fibromyalgia
in the secondary FMS group."
"What could possibly
be the source of elevated NGF in primary FMS?" asks Larson. Of
equal importance, one has to wonder: Does the elevated NGF cause the
elevation in substance P and the other symptoms seen in people with
FMS? Providing answers to these essential questions was the main focus
of Larson's AFSA-funded project awarded in 1998. Larson administered
NGF into the spinal fluid of mice and then measured their responses
to a number of tests. For example, she looked at tail flick latencies,
which is the time it takes for a mouse to respond to a thermal stimulation
of the tail. After the infusion of NGF, the mice responded much quicker
and this hypersensitivity state lasted for several days. Further details
of the AFSA-funded study are provided in the article that follows. Suffice
it to say, elevated NGF in the spinal fluid does cause hyperalgesia,
but the situation is much more complex.
"We could have just
administered NGF to our mice and said, This is our model for fibromyalgia'
because it produces hyperalgesia," claims Larson. But as she has
already pointed out, FMS is not just a pain sensitivity problemit
is so much more. Further evaluation of the mice revealed that stress
did not intensify their pain, they did not exhibit any evidence of a
sleep disorder, and they did not have any of the other symptoms often
associated with FMS in humans. Basically, Larson was successful in generating
a chronic pain model, but it was not a model for FMS. Many of the associated
symptoms of FMS were missing and the presence of elevated NGF in the
spinal fluid could not be explained. Ordinarily, NGF is generated in
the periphery when there is damage to the tissues, and then it is transported
back to the spinal fluid by the neurons that are in the area of the
tissue trauma. Yet, significant tissue damage is not seen in patients
with primary FMS, so this ruled out peripheral NGF as the cause of the
syndrome. (In fact, Larson's research casts doubt on the strongly
held notion that elevated levels of substance P and NGF cause FMS. These
substances likely play a role in generating the symptoms of FMS, but
something else is causing their elevated production.)
What if the "damage"
occurred within the central nervous system? This would produce elevated
NGF in the spinal fluid. However, Larson says that situations that could
cause a significant elevation of NGF would have to be very dramatic,
such as meningitis, and this just is not seen in FMS patients. Spinal
stenosis (a narrowing of the spinal canal caused by disk or vertebrae
impingement) could possibly contribute to a small fraction of people
with FMS, but certainly not all of them. Something else has to be causing
the elevations of NGF.
Mast Cells in the Thalamus
After performing an extensive
literature search, Larson says she was "excited when she ran across
the fact that there are cells within the central nervous system (CNS)
that can synthesize NGF. Those are mast cells." Mast cells are
usually located in areas of inflammation or allergic reactions. They
are created from bone marrow and shipped out to the tissues as part
of the immune response system and Larson says, "You don't think
of mast cells as being in the CNS." She adds that because their
function in the CNS is not understood, it is easy to overlook them.
As it turns out, the mast
cells aren't just scattered randomly throughout the CNS; they are concentrated
in the thalamus. This would make sense for FMS. The thalamus influences
the function of the hypothalamic-pituitary-adrenal (HPA) axis, which
is one of the body's primary stress response systems. The thalamus is
also involved in pain transmission, sleep modulation, and many different
sensory pathways such as hearing and vision. When pain signals travel
up the spinal cord neurons en route to the brain, they arrive at the
thalamus (via the spinal-thalamic tracts) and from there, the signal
is relayed by the thalamus to various parts of the cortex. The thalamus
appears to be the area where there are problems in FMS, and this just
happens to be where the NGF-producing mast cells are located in the
mammals studied thus far.
The location of the mast
cells appears to be consistent with FMS findings, but what about the
elevated levels of substance P in the spinal fluid? Is there a link
between the mast cells in the thalamus and elevations in substance P?
As it turns out, the substance P-containing fibers that are known to
transmit pain can also attract mast cells like a magnet attracts iron
particles. In addition, substance P is known to "degranulate"
or break mast cells apart. This happens when the mast cells are activated
(by the substance P) and it causes a release of their contents, which
in turn, leads to inflammation and histamine buildup in the region.
It's also important to note, mast cells are not like white blood cells,
which get activated, become degranulated, and then they are history.
Mast cells degranulate in the presence of substance P, but then they
often turn around and resynthesize their granular contents, and they
are back in action. They go through this process countless times and
have a relatively long life in the body.
The foregoing explanation
of how mast cells operate, especially when activated by substance P,
is well-documented for mast cells in the peripheral tissues. Yet, FMS
is a problem within the CNS, where substance P and NGF are elevated.
Not as much is known about how masts cells operate in the thalamus,
but Larson hypothesizes that it is similar to that in the periphery.
In other words, substance P causes degranulation (or a bursting) of
mast cells in the periphery, so substance P is thought to exert the
same effect on the mast cells in the thalamus. With an abundant supply
of substance P in the spinal fluid (threefold elevation in FMS), it
may be able to cause continual degranulation of mast cells in the thalamus
and trigger a cascade of symptoms ... possibly FMS.
How Does the Theory Hold Up?
In order for the thalamic
mast cell hypothesis to hold up, these cells need to respond in a fashion
that mimics the clinical symptoms and findings in people with FMS. First,
it is known that these cells produce NGF, which can then trigger the
production of substance P. This could account for the elevated levels
of these two compounds in the spinal fluid of FMS patients. Secondly,
as Larson presented her model, she addressed the following six factors:
(1) symptoms triggered and/or made worse by stressors, (2) gender differences
to explain the high female predominance, (3) hormonal influence (women
with FMS anecdotally claim that symptoms are worse during the second
half of their menses cycle), (4) blood flow changes in the thalamus,
(5) modulation of sleep function (sleep is often disturbed in people
with FMS), and most important of all, (6) modulation of pain. A brief
rundown of how each factor fits into the model is provided in the paragraphs
Mast cells are most commonly
known to rush to the site of parasitic infections and places where allergic
reactions occur. This automatic response to these types of stressors
causes mast cell degranulation (e.g., breaking apart to expose their
guts) and a series of immunologic reactions, such as inflammation and
histamine release. But this is just one of many different ways in which
mast cells are linked to stressors. "What a lot of people don't
know," says Larson, "is that stressors that activate the HPA-axis,
which then causes the release of corticotropin-releasing hormone (CRH),
are very active on mast cells and can cause their degranulation."
Another molecule that has recently been discovered, called urocortin,
is even more potent than CRH in its ability to cause mast cell degranulation
during stressful situations. Larson cautions that stress is often misinterpreted.
It is not just tightened muscles or feeling distraught; stress is a
chemical reaction that can activate many diseases, such as psoriasis
(and other skin disorders), interstitial cystitis, and irritable bowel
syndrome. In the case of FMS, Larson's theory is that this chemical
reaction and release of CRH or urocortin is occurring in the brain's
If the mast cells in the
thalamus play a causative role in FMS, then one would expect differences
in them between the genders because FMS is far more prevalent in women.
Comparing males to females, the number of mast cells in the thalamus
of mice were the same. However, mast cells tend to aggregate in certain
areas within the thalamus, and this is where the differences between
the genders became apparent. Larson found three specific areas in the
thalamus of female mice where the mast cells congregated, and this pattern
was not found in males. In fact, in one of the areas, there were absolutely
no mast cells in the male mice (comparing 15 male mice to 16 females).
These areas happen to be important for pain transmission as well as
communication between the spinal cord neurons and the thalamus. So the
dramatic difference in mast cell distribution between the genders may
help account for the higher prevalence of women with FMS pain.
What about hormonal influences?
Based on several elaborate studies done by Larson, she found that estrogen
tended to recruit mast cells to specific areas in the thalamus and progesterone
caused their degranulation. The degranulation causes an immunologic
responsenot in the peripheral tissues but rather, in the thalamus
(the center of the brain).
Do mast cells play a role
in blood flow? Yes. Mast cells have been studied in cancer research
because they enhance the blood flow to the area of the tumor. Without
sufficient oxygen and nutrients, the tumor would die. Looking at this
from a different perspective, from the thalamus in the brain where the
mast cells in patients with FMS are hypothesized to play a causative
role, these cells may cause a change in blood flow. Pain signals carrying
substance P could degranulate them and reduce their ability to enhance
blood flow. This corresponds to studies by Laurence Bradley, Ph.D.,
(another AFSA-funded researcher), showing that pain stimuli significantly
alter blood flow in the thalamus in people with FMS.
The mast cells in the thalamus
secrete NGF and they degranulate when substance P-containing neurons
terminate in the thalamus. This occurs during situations of stress and
pain, making the pain worse. It also has ramifications for disturbing
sleep. "Histamine is a major compound in mast cells," says
Larson, "and it is released upon degranulation. Histamine is a
stimulant in the CNS; it causes arousal." So stress can modulate
both pain and sleep in Larson's model, which mimics what happens in
How do substance P, NGF,
dynorphin and serotonin affect mast cells in the thalamus to actually
cause FMS? Can an animal model be generated from this hypothetical "paper"
model? These are two of the many questions that Larson plans to answer
in her studies over the next five years. She also hopes to answer relevant
questions about pain transmission in fibromyalgia as well as clarify
the role that these stress- and hormone-sensitive mast cells in the
thalamus might be playing.
FMS: Chronic Effects of NGF in the Spinal Cord
In 1998, Alice A. Larson,
Ph.D., Professor of Pharmacology and Neuroscience at the University
of Minnesota, was awarded a grant to study the effects of infusing NGF
into the spinal fluid of mice to determine if this might generate a
good animal model for FMS. The funding by AFSA was just the beginning
of a very ambitious and much-needed study to better understand the role
that chronically elevated levels of nerve growth factor (NGF) play in
the development and perpetuation of the symptoms of FMS. Indeed, patients
with FMS have an elevation of both NGF and substance P (SP) in their
spinal fluid. Based upon the knowledge that NGF could cause elevations
of SP and increase pain, Larson hypothesized that mice with artificially
elevated levels of NGF could serve as an animal model for people with
FMS. Upon hearing the mind-boggling presentation by Larson at the "Focus
on Pain" meeting in Orlando, FL, one could certainly state that
the AFSA project conducted by Larson was the start of many good studies
"Our grant from the
American Fibromyalgia Syndrome Association, entitled Fibromyalgia:
Chronic Effects of NGF in the Spinal Cord, was pivotal in generating
the preliminary data that was necessary to obtain our current funding
from the National Institutes of Health (NIH)," says Larson. "This
award, entitled Role of Neurotrophins in an Animal Model of Fibromyalgia,
focuses on the role of NGF in the spinal fluid of patients with fibromyalgia.
Our approach is to correlate various conditions in animals that may
produce a long-term hyperalgesia (enhanced pain sensitive state) with
changes in growth factors, targeting muscle pain and gender-dependent
differences as important variables."
During the speech in Orlando,
Larson indicates that while chronic infusion with NGF generated a model
for chronic pain or hyperalgesia, it was not FMS. This is an important
distinction because Larson explains that FMS is more than just having
enhanced pain perception! There are problems with sleep, cognition,
modulation of symptoms by stress (including infections and physical
exertion), gender differences (any model would have to explain why FMS
occurs more often in females), and a number of other variables that
make fibromyalgia a syndrome.
Larson generated rather surprising
data with her small-scale AFSA study and the NIH funding allowed for
her to confirm her findings and expand the scope of her work. The actions
of SP are not so straight forward. SP splits into two types of metabolites
or compounds: one that is thought to relieve pain, called SP(1-7), and
one that is thought to be the cause of all of the pain problems produced
by SP, called the C-metabolite. In a report by Larson and colleagues,
the actions of SP are not so simplistic.3 The "good"
metabolite under most conditions relieves pain, but not always. Also,
newly designed drugs that block SP (NK1 receptor antagonists)
don't obliterate pain, but are involved in hyperalgesia. These drugs
are soon going to be available on the market and have already been tested
in an AFSA-funded study conducted by Luc Jasmin, M.D., Ph.D. The bottom line: they will boost the action of opioids, but they won't
be the panacea for treating FMS (see Jasmin's project description).
Another avenue of investigation involves cloning the SP(1-7) receptor
to capitalize on the pain-relieving aspects of SP(1-7) type of molecules. John Stewart, Ph.D., is already working on an AFSA-funded study
with this goal in mind.
In addition to the work outlined
at the Orlando meeting, Larson is also involved in studying another
interesting compound, kainic acid. It is not produced in humans, but
kainic acid can be easily tested in mice to determine if similar compounds
that activate the same receptor may be somehow involved in FMS pain.
"One of the papers that has resulted from this work was done in
collaboration with Dr. Luc Jasmin, another researcher who has been funded
by AFSA," says Larson. "These studies focus on the long-term
hyperalgesic effect of kainic acid, a compound that can be used to selectively
study certain excitatory amino acid receptors that are hypothesized
to be involved in FMS pain.4 We had previously shown that
kainic acid produces a persistent hyperalgesia in both rats and mice
when injected under the skin.5 In collaboration with Jasmin,
we have now found that this effect is likely mediated by an action on
the vagus nerve." Larson also found that activation of the kainic
acid receptors interfered with morphine's effectiveness to reduce pain
in mice. Mice that lack noradrenaline also tend not to respond as well
to morphine analgesia, as indicated by Dr. Jasmin's work.
What does this mean? Larson
explains that "excitatory amino acids (EAAs) are molecules normally
found inside all cells where they are used for protein synthesis. When
cells burst, as during tissue damage or mast cell degranulation, EAAs
are released into the surrounding tissues where they can interact with
EAA receptors on the cells that they come into contact with. The receptors
are located on the surface of neurons and the EAA or kainic acid molecules
interact with these receptors like a lock and key fit. This activity
on a specific type of EAA receptors, in this case the kainic acid receptors
on the vagus nerve, is what we think causes hyperalgesia. The vagus
nerve is important because it carries autonomic information from the
gut, heart, immune system, etc. It regulates autonomic function (which
is not working well in patients with FMS) and the vagus nerve also carries
appropriate reflex information.
"This study may have
relevance to fibromyalgia as many FMS patients have inflammatory conditions
in the GI tract where the vagus nerve projects. Wounds are known to
contain elevated concentrations of excitatory amino acids that could
mimic the action of kainic acid. Our ongoing studies are examining the
fiber type that is involved in the hyperalgesic condition produced by
As part of Larson's work
on EAAs, she found evidence for increased production of nitric oxide
(NO) in the spinal fluid of people with FMS and credited AFSA for providing
partial funding assistance.6 "Molecules similar to kainic
acid and activated NMDA receptors in the spinal fluid can both induce
NO synthesis," says Larson. "We measured a variety of amino
acids in these spinal fluid samples of patients to see what picture
emerged" (citruline, an amino acid that is co-produced along with
NO, was elevated). Although a small pilot study by Laurence Bradley,
Ph.D., shows that NO is elevated in the blood of FMS patients, this
molecule in the periphery does not perform the same functions as it
does in the CNS where it is involved in pain transmission. "Peripheral
NO," says Larson, "is involved in vasodilation of the vasculature
and does not reflect the same pool of NO as that in the central nervous
Summing up the meaning of
her AFSA grant and how it has influenced her research, Larson says:
"The success of the award from AFSA cannot be measured merely in
publications at this time. Most of the work that resulted from that
study is not yet published, but is being extended by our ongoing work
funded by NIH. We have a mixture of some promising data as well as surprises
that have led to even more questions about the basic assumptions that
prevail in the pain literature. For example, for many years, we have
assumed that because SP is released in the spinal cord in response to
pain transmission, it must be important in the mediation of this sensation.
Now, of course, we know that this data is correlational only and that
acute pain is not influenced by compounds that antagonize SP (such as
the neurokinin-1 or NK1 receptor antagonists). In fact, it
is the enhanced pain (hyperalgesia) experienced during chronic pain
conditions that is attenuated by these compounds.
"Based on our recent
findings, it would appear that the role of SP is merely modulatory.
This raises the question, what is the role of the elevated SP found
in the spinal fluid of patients with fibromyalgia? While the mediation
of hyperalgesia may be the simple and widely accepted answer, we have
recently found that the metabolites of SP are able to increase the density
and distribution of the SP receptor (NK1) in the rat spinal
cord.3 This suggests that the release and accumulation of
SP metabolites during pain transmission feeds forward' and promotes
the synthesis of sites that serve to modulate pain transmission. While
this in and of itself is not remarkable, it is noteworthy that this
increase in production of NK1 sites occurs simultaneously
with the development of an antinociceptive (analgesic/pain-relieving
in humans) condition when tested in these same rats. If SP interacting
with NK1 sites is important in hyperalgesia, one would predict
the exact opposite.
"You can see how this
work, done simultaneously with the AFSA project, put our whole interpretation
of the relationship between NGF, SP and the metabolites of SP in question.
Our results from the AFSA study did not clarify the issue, so we decided
not to publish at that time to avoid cluttering the literature with
mere data, but to try to continue work to discover a likely interpretation
of our findings. So we used the data from the AFSA study to procure
an NIH award to further our work to look for more conclusive answers
regarding the role of NGF and its relationship to SP. (As mentioned,
a portion of our findings now appear in print.3)
"I'm afraid that the
answers are not as simple as we had originally thought. What does all
this mean to patient who are suffering with fibromyalgia? I'm ever
hopeful that when the maze appears to be the most convoluted, that we
may be nearing the center, a point from which the whole pattern may
unravel. Having been sufficiently perplexed with our results over
the past few years, I wrote a review of the research in the field in
the hopes of finding a lead that we may have originally missed.7 During this process we have come across many possible suspects'
that we are now more fully investigating. So, while perplexing data
may at first appear to be a setback, it has served to redirect our efforts,
perhaps to a more fruitful direction. I hope this summary helps to put
our recent publications in perspective.
The Role of Zinc in FMS Pain
Beginning in 1997, I.
Jon Russell, M.D., Ph.D., at the University of Texas in San Antonio,
initiated a pilot study to investigate the possible role of zinc, a
trace mineral, in the production of FMS pain as well as other symptoms.
Why look at zinc? It is known to be essential for the development of
the central nervous system, its largest concentration in adult humans
is found in the brain's hippocampus (the primary region being investigated
by Patrick Wood, M.D., see Brain Imaging section), and
this element is known to be involved in both memory and pain transmission.8 In addition, zinc may help block the activation of the NMDA receptors
in the spinal cord that are thought to be responsible for magnifying
the pain of FMS. Zinc also appears to play an assistive role in the
development of persistent pain (hyperalgesia) that is caused by the
activation of kainic acid receptors.9 Ordinarily, kainic
acid receptors are not activated, but a just-published study by Alice
Larson, Ph.D., points to the possibility that this pain-producing
mechanism may be important in the development of chronic pain, such
as FMS.4 Certainly, the role of zinc is not clear-cut. A
deficiency could explain some of the pain in FMS, but too much zinc
could create problems as well.
Russell conducted an investigational
study to determine if patients with FMS might be deficient in zinc.
He hypothesized that if patients were low in zinc, that this could explain
some of their symptoms, particularly pain. Given that zinc is found
in numerous areas in the body, one can't simply take a blood sample
to get an accurate reading on a person's zinc stores. This meant that
Russell had to perform a short "loading test" in which 30
FMS patients and 30 healthy matched controls were given a specified
amount of zinc to take during a 48-hour period. He measured plasma zinc
values before and after the loading test. The increase in the amount
of plasma zinc levels is a rough estimate of the zinc nutritional status
of the study participants (both the FMS patients and the healthy subjects).
In other words, the greater the increase in the plasma zinc level, the
greater the suspected zinc deficiency.
At the October 1999 meeting
of the American College of Rheumatology, Russell presented the preliminary
findings of his AFSA-funded study. He did find that people in the FMS
group were more likely to have a larger increase in their plasma zinc
levels during the loading test, compared to healthy control subjects.
Naturally, one might ask if lower-than-normal zinc levels may play a
role in the painful symptoms of FMS, but the answer is complex. Dr.
Russell kindly provided an answer to this question in a report to AFSA
and it is reprinted below to help you understand the complicated dynamics
of the situation.
Are fibromyalgia patients zinc deficient?
"This is a difficult
question because deficiency of zinc in the medical literature has taken
so many different clinical forms. Severe deficiency in children has
resulted in growth retardation and a number of other developmental abnormalities.
In adults, a recognized manifestation can be loss of smell and taste.
Fibromyalgia patients do not typically complain of loss of taste or
smell. Perhaps zinc deficiency in the presence of some other abnormality,
such as high substance P, can result in more pain than loss of taste
and smell. The literature is replete with controversy about zinc deficiency
because its levels are usually measured in the blood. Blood zinc levels
are highly regulated and may be normal in spite of chronic total body
deficiency. It seems likely that this question will require considerable
additional study to clarify it with confidence. The first step would
be to repeat the present study with a comparable or larger number of
subjects, using a larger exposure to zinc. The goals would be to confirm
zinc deficiency at the onset, estimate the magnitude of the total body
deficit of zinc, replace zinc by dietary supplementation until the deficit
has been normalized, and monitor carefully to determine whether the
painful symptoms respond to zinc replacement."
Russell also points out that
while he tested plasma zinc levels (before and after the 48-hour zinc
loading period) the spinal fluid levels in patients may produce different
information. "The abnormality may be even more dramatic in the
spinal fluid as is the substance P," says Russell. This study has
generated interesting findings but only a small number of individuals
were tested and it was conducted on a short-term loading basis. It would
be unwise to advise patients to take zinc because the effects (and side
effects) on its chronic, daily use remain to be determined. Still, the
results of this project can serve as an important basis for future investigations.
Cloning a Receptor for New Drug Development
In 1998, AFSA received an application that proposed something entirely
different from the other proposals received so far in the organization's
history: cloning a "pain-relieving" receptor for developing
a new FMS/CFS drug. The applicant, John Stewart, Ph.D., of the
University of Colorado Medical School in Denver, proposed the cloning
of the receptor for one of the metabolites of substance P (SP). SP is
a pain transmitter in the central nervous system and its threefold increase
in the spinal fluid of patients with FMS has been measured by four different
research laboratories. Original work by Stewart demonstrated that in
the brain, SP is split into two major compounds: one that causes pain
(the C-metabolite) and one that in many cases may relieve pain (SP(1-7)
or the N-metabolite). NGF is also involved and the situation is more
complicated than initially thought. A diagram of the process is illustrated
Rodent studies by Stewart
and AFSA-funded researcher Alice Larson, Ph.D., indicated that
SP(1-7) can produce substantial pain relief. The results depend upon
the type of test used and the information cannot be "perfectly"
extrapolated to humans. Still, the pain-producing effects of the C-metabolite,
and the possibility that drugs acting on the SP(1-7) receptor could
cause substantial pain relief, begs two important questions: (1) Why
hasn't the pharmaceutical industry developed a drug to block the "bad"
pain-producing metabolite of SP, and (2) Why haven't they focused on
the potential "good" metabolite, SP(1-7)? The situation isn't
At least three major drug
companies have developed their own patented version of an SP receptor
blocker (referred to as a neurokinin receptor antagonist, or an NK1 drug). First, the NK1 receptor had to be cloned, and then
the drug industry developed compounds to block its action. After several
years of trying to demonstrate the pain-relieving effects of NK1 receptor blocking drugs, the outcome has been disappointing. The only
glimmer of hope in this area came from AFSA-funded researcher Luc
Jasmin, M.D., Ph.D., who was able to demonstrate in mice that the
NK1 drugs may work exceptionally well in relieving FMS painas
long as the medication is used in conjunction with an opiate (at least
a low dose) and a drug that boosts the levels of noradrenaline (there
are many meds that do this). Jasmin's phenomenal work in mice still
needs to be replicated in patients with FMS once the NK1 drugs reach the marketplace at the end of 2003. However, it is a major
breakthrough that was made possible with funding assistance from AFSA.
Despite Jasmin's accomplishments, patients may face two potential obstacles:
(1) the inability to convince their physician to prescribe an opiate
on a regular basis and (2) the undesirable side effects that limit the
use of opiates in many patients.
Stewart is working on an
entirely different approach to combat the elevated SP problem. He is
cloning the SP(1-7) receptor so that novel drugs that either block (turn
off) or bind (turn on) this receptor can be studied. This means developing
drugs that are completely different from the NK1 class of medications.
SP breaks down into its "bad" metabolite that produces pain,
and its "good" metabolite that relieves pain in certain situations.
While the drug industry has been focused on trying to block the "bad"
metabolite known to produce pain, Stewart is working to clone the receptor
for the "good" metabolite SP(1-7) that relieves pain.
This is a tedious, high-tech
process, but Stewart has a proven track record. His previous work has
led to the discovery of compounds that may produce new drugs to treat
cancer. One of his compounds is in development at the National Cancer
Institute for lung cancer.
Stewart is well on his way to developing the SP(1-7) receptor clone,
but this is not a project that can be rushed. He has evidence that the
rat brain has the "message" (mRNA) for the SP(1-7) receptor
among its thousands of messenger RNAs. He fractionated total mRNA into
a library of 400 fractions and is now testing each one in order to find
the correct clone and determine the exact chemical structure of the
Stewart reports that he is
well into the receptor testing phasemore than halfway through
the project. Once completed, he will determine the exact amino acid
sequence of the SP(1-7) receptor, and will seek additional funding from
the NIH for developing a bio-active drug to treat FMS/CFS pain ... just
as he has done before in the field of cancer.
Commenting on the importance
of his work, Stewart says: "Completion of this project will open
a novel and very exciting pathway for the development of new fibromyalgia
drugs that will not produce the unwanted side effects of any of the
currently available medications. Using the new molecular tools developed
in this AFSA-funded project, we will be able to discover new drugs to
treat other serious illnesses as well, such as Parkinson's and Alzheimer's
While the forgoing discussion
explains the science behind Stewart's award, his answers to a few additional
questions will enable you to fully understand why this grant is so important.
has AFSA's award meant to you?
It has been the key to letting me work on this project I have wanted
to do for many years. Three years ago I made a deal with my department
chairman. I told him that I would accept early retirement but continued
to teach (I have 130 med students!), as long as he would let me use
the funds otherwise paid to me in salary to hire people for the lab.
Thus, we have salary funds for the two people working on the project,
but we still needed outside funds for supplies for the project to proceed.
This arrangement means that we can accomplish much more with the limited
AFSA funds, since we don't have to pay salaries out of the award ...
and it also allows me to oversee a project that I have been interested
in doing for several years.
is it enabling you to accomplish that you may not have been able to
Since so few people believed in us about the analgesic action of SP,
there is no way I could have otherwise received the funds needed. I
am very grateful to AFSA for making this important project possible.
will patients benefit from your study once it is completed and what
new avenues of research will result from it?
Although new drug development is a lengthy process, eventually there
will be a totally new class of analgesics to help treat patients with
FMS based on this work. Since these new agents, such as SP(1-7) receptor
antagonists, will work by a mechanism totally distinct from those of
current analgesics, they should provide excellent complements to existing
drugs for pain control.
Blocking Substance P ... Will it Work?
Drugs that block the pain-transmitting
action of substance P will soon be on the market. The natural question
is: Will they be effective at taming the pain of FMS? Pain neuroscience
researcher Luc Jasmin, M.D., Ph.D., at the University of California
in San Francisco, had the daunting task of determining how substance
P blockers (called NK1 receptor antagonists), noradrenaline
and opioids might work together, or individually, to treat chronic pain.
Jasmin already had an NIH grant to look at the effects of short-term
depletion of noradrenaline (NA) in mice. He found that this led to elevated
levels of substance P in the central nervous system and enhanced pain
sensitivity. In other words, it seemed as though Jasmin had developed
a "temporary" model for FMS, but a more stable model was needed
in order to test the effects of different drug interactions.
"The June 2001 AFSA
award was essential for conducting our study on mice that lack NA,"
says Jasmin. These mice had a genetic abnormality that interfered with
their ability to manufacture NA, so they represented a more "stable"
model. Commenting further, Jasmin says, "This study, entitled Noradrenaline
Deficient Mice as a Model for Fibromyalgia, was entirely supported
by AFSA funding and would not have been done without this support. The
results are key to our scientific understanding of the role of NA in
pain, in the control of substance P release, and in opioid analgesia."
One primary study that examines
the impact of NA on the development of substance P-related pain and
responsiveness to morphine in mice has already been published (supported
in part by AFSA).10,11 Jasmin and his colleague, Peter
Ohara, Ph.D., found that these specially bred mice, which lacked
NA and had elevated levels of substance P in their central nervous system,
had a reduced analgesic response to morphine. In other words, these
mice did not respond as well to opioids as they should have. In many
ways, these mice were similar to humans with FMS.
Patients with FMS have been
shown to have low levels of NA and elevated levels of substance P in
their spinal fluid. They also have low pain thresholds and while patients do respond to opioids, this class of drugs doesn't come close
to eradicating the pain. Given this situation that tends to parallel
the NA deficient mice, Jasmin looked for ways to improve their pain
thresholds as well as their responsiveness to opioids. His intent was
to search for treatment methods that might be useful for FMS.
Jasmin found that there were
two different ways to enhance the pain-relieving effects of opioids.
One way was to increase the central nervous system level of NA (many
tricyclic antidepressants do this, i.e., amitriptyline). NA works by
inhibiting the release of substance P, which can lessen a person's pain.
Yet, drugs that raise NA levels don't provide nearly enough pain relief.
This may be explained by Jasmin's second finding: that NK1 receptor antagonists worked just as well as NA to raise pain thresholds
in the mouse and restore the efficacy of morphine.
morphine efficacy by NK1 antagonists," says Jasmin,
"indicates that substance P is released despite the presence of
morphine." This means that when NA is low and substance P is high
(a situation found in FMS patients), morphine and other mu-opioid agonists
will not be as effective as they ought to be. Jasmin proposed that substance
P and opioids have opposite effects on pain; the former works to increase
pain while the latter works to diminish it.
One implication of Jasmin's
work is that the soon-to-be-released NK1 drugs may play an
essential role in the treatment of FMS, but not by themselves. The greatest
benefit of NK1 meds may be achieved when they are used in
combination with opioids as well as drugs that raise the level of NA
in the central nervous system. Since Ultram (tramadol) works as a mild
opioid and increases NA (along with serotonin), Ultram plus NK1 receptor antagonists may prove highly effective in treating FMS. It
is also possible that NA-elevating drugs that also reduce substance
P may work well in conjunction with NK1 agents. Zanaflex
(tizanidine) would be such an agent and it has been shown in a small
drug trial to reduce substance P in the spinal fluid of patients with
FMS. This drug also displays muscle relaxant properties, which patients
with muscle pain may find beneficial.
on Jasmin's work with NA-deficient mice, the interactions of substance
P, opioids, NA, and NK1 drugs (which work to block substance
P) can be summed up in the accompanying diagram. Opioids and substance
P produce opposite effects on pain. In conditions in which substance
P is elevated (e.g., FMS), the "pain balance" can be restored
by increasing NA and/or adding an NK1 antagonist. As you
can see, Jasmin's findings open the door to multiple approaches that
may be beneficial in targeting FMS-like pain.
Delving further into NA's
role in chronic pain, Jasmin's studies in mice establish that a dysregulation
of NA transmission can lead to chronic pain. In addition, Jasmin's NIH-funded
experiment that temporarily blocked the action of NA-producing neurons
with a chemical agent served to confirm the results of the AFSA-funded
study with NA-deficient mice. Part of this work was recently published
in Journal of Comparative Neurology.12 "Overall,"
says Jasmin, "the role of NA in chronic pain is a much more subtle
one than previously thought, based on other types of short-term or acute
"The take home message,"
according to Jasmin, "is that, in contrast to previous suggestions
that NA is a necessary neurotransmitter of the endogenous pain-inhibitory
system, our results indicate that NA contributes minimally to determining
one's pain threshold." He also found that the pain-fighting effects
of NA work in conjunction with opioids and substance P blocking drugs,
as already discussed above.
"One of the most important implications for patients," says
Jasmin, "is that this works demystifies some of the obscure concepts
of pain. Despite its subtle role, NA exerts some very specific functions
that can improve our understanding of pain, allow us to design new treatments,
and more importantly, show how a single defective neurotransmitter can
be responsible for a number of apparently unrelated disorders. A decrease
in NA leads to a lowered pain threshold, sleep, memory, hypothalamic-pituitary-adrenal
(HPA) axis regulation and autonomic dysfunction. Doesn't this sound
similar to FMS?"
Jasmin is using the studies
carried out with AFSA funding, as well as his larger NIH study, to provide
the basis for a new NIH grant application. His work with NA-deficient
mice will be followed up by studying the contribution of NA to the pain-relieving
effect of antidepressants (which raise the central nervous system levels
of NA and/or serotonin and are often prescribed for patients with FMS).
"Below is the summary of a proposal recently sent to NIH,"
says Jasmin, "to give you insight on where we are headed with regards
to future studies:"
(ADs) are among the few drugs that effectively, although moderately,
treat chronic pain, there is a great need to understand their precise
mechanism of action in order to improve their analgesic efficacy. ADs
work by decreasing the sensory and emotional components of pain. The
neurotransmitter noradrenaline (NA) is essential to both components.
AD's analgesic effects likely depend on NA acting in different brain
areas, yet the contribution of specific brain areas remains largely
unknown. Take for example, the cerebral cortex, the structure that forms
the outer shell of the brain (see the diagram in the Brain Imaging section).
It seems likely that the cortex is the target for the analgesic action
of ADs, since studies have shown that reduced NA in the brain's cortex
leads to increased pain. Other brain structures that appear more closely
linked to the anti-anxiety effect of ADs are the hypothalamus and amygdala.
These two structures are part of the limbic system in the brain and
they receive inputs from the thalamus. In these two areas, ADs induce
changes in gene expression as well as alter the response of neurons
expressing corticotropin-releasing hormone (CRH). CRH is a key neuro-hormone
that controls the body's of stress responses by acting through the HPA
system. It is unclear if NA is involved in this process and this needs
to be explored.
"The guiding hypothesis
of our proposal is that NA in the cerebral cortex is essential to
the pain-relieving effect of ADs, implying that chronic pain and
non-responsiveness to treatment involve a lack of cortical NA. In other
words, animal models as well as patients with FMS should theoretically
have low NA levels in the cortex region of their brain. As it is not
uncommon for anxiety to complicate chronic pain, we will identify which
brain areas NA acts as an analgesic and which brain areas it acts mostly
to relieve anxiety. Because part of the analgesic effects of ADs is
believed to depend on opiates, we will also test whether the synergistic
effect of combining ADs and opiates is dependent on NA. As a correlative,
we will determine if ADs alter specific molecular markers in the hypothalamus
- Laughlin TM,
Larson AA, Wilcox GL. J Pharmacol Exp Ther 299(1):6-11, 2001.
- Giovengio SL,
Russell IJ, Larson AA. J Rheumatology 26(7):1564-9, 1999.
- Velazquez RA,
et al. Eur J Neuroscience 16: 229-241, 2002.
- Tien et al. Pain
- Giovengo SL,
et al. Pain 83: 347-358, 1999.
- Larson AA, et
al. Pain 87(2):201-11, 2000.
- Larson AA and
Kovacs KJ. Current Pain Headache Rep 5: 338-346, 2001.
- Velazquez RA,
Cai Y, Shi Q, Larson AA: The distribution of zinc selenite and expression
of metallothionein-III mRNA in the spinal cord and dorsal root ganglia
of the rat suggest a role for zinc in sensory transmission. J Neuroscience
- Larson AA, Giovengo
SL, Shi Q, Velazquez RA, Kovacs KJ: Zinc in the extracellular area
of the central nervous system is necessary for the development of
kainic acid-induced persistent hyperalgesia in mice. PAIN 86:177-184,
- Jasmin L, et
al, PNAS 2002; 99(2):1029-1034.
Downloadable free at: www.pnas.org/cgi/content/abstract/99/2/1029
- Hill R, PNAS
Downloadable free at: www.pnas.org/cgi/content/full/99/2/549
- Jasmin L, et
al. J Comp Neurol 460:38-55, 2003.
[Back to Table of Contents]
In the early to mid-nineties,
researchers raised the question about whether FMS (as well as CFS) might
be a neuroendocrine condition. Abnormalities in the hormonal secretions
from the pituitary gland had been uncovered. For example, Leslie
Crofford, M.D., of the University of Michigan in Ann Arbor, found
abnormalities in the stress response mechanisms involving the hypothalamic-pituitary-adrenal
(HPA) system. Robert Bennett, M.D., of OHSU in Portland, found
that one-third of FMS patients met the criteria for adult growth hormone
deficiency syndrome. Daniel Clauw, M.D., previously at Georgetown,
but now at University of Michigan in Ann Arbor, was interested in testing
a neurological system that interacted with the HPA axis called the autonomic
nervous system (ANS).
As you can see from the diagram
below, both hormones and neurotransmitters are involved in the regulation
of the ANS and the same holds true for the HPA system. That is why this
section is called Neuroendocrine Findings and the results obtained by
two AFSA-funded researchers are described in this section.
Melatonin in Patients with FMS and CFS
The rheumatologist and principal
investigator Leslie Crofford, M.D., collaborated in 1996 with
another neuroendocrine scientist, Ania Korszun, M.D., Ph.D.,
in a successful project to determine whether the abnormalities in cortisol
production were due to problems with melatonin production. The results
were subsequently published in the Journal of Rheumatology in
December of 1999.1 An overview of the study findings and
an explanation of their significance are provided by Crofford below.
"Our study was the first
on circadian phase of patients with FMS and/or CFS. Our findings have
subsequently been confirmed by a research team at Harvard, whose published
report appeared in 2001.2 Melatonin is involved in synchronizing
the circadian (24-hour) rhythms controlled by the brain by acting as
an interface with environmental cues such as the light-dark cycle. When
your eyes see light in the morning, this shuts off the production of
melatonin by the pineal gland in the brain. In situations where desynchronization
of biological rhythms occur (e.g., jet lag or people working odd shifts),
symptoms of fatigue, cognitive dysfunction, and depression can occur.
Some of the neuroendocrine hormones that are disturbed in FMS and CFS,
particularly the stress hormone cortisol, have a strong circadian rhythm.
Therefore, we asked whether there was evidence of desynchronization
of the melatonin and cortisol rhythms that might provide clues to the
neuroendocrine biology of FMS and CFS. In other words, perhaps an abnormally
low or out-of-sync production of melatonin might be at least partially
responsible for some of the symptoms of these two overlapping syndromes.
"In the study funded
by AFSA, we asked whether the level of melatonin was altered and we
also looked to see if its production was out of rhythm from that of
cortisol in patients with FMS and/or CFS. We found that melatonin and
cortisol rhythms did not differ significantly with respect to their
phase in patients with FMS or CFS compared with controls subjects, although
the time between peaks of these two hormones was longer in patients
than controls. Furthermore, rather than lower melatonin levels, patients
with FMS, but not those who only met the criteria for CFS had higher
melatonin levels during the overnight peak. Taken together, we conclude
that the symptoms of FMS are not related to circadian phase shift nor
a deficiency of melatonin.
"The lack of significant
circadian phase shift in FMS was later confirmed by Gail Adler, M.D.,
Ph.D., at Harvard University.2 This study looked at three
measures throughout a 40-hour period: melatonin in the blood, cortisol
in the blood, and core body temperature. Actigraphs (devices placed
on the wrist to monitor movement) and a controlled diet were also implemented.
Comparing the circadian rhythms of cortisol, melatonin, core body temperature,
and sleep/wake data from the actigraphs, the authors also concluded
that symptoms of fatigue, sleep disturbances, and cognitive dysfunction
were not caused by abnormalities in the body's circadian rhythm.
as a sleep inducing agent may still be helpful in some patients with
FMS and CFS. This issue has not been examined directly in a controlled
clinical trial, although a small uncontrolled trial implied that some
patients benefited from this therapy for reasons that can't be explained
by circadian rhythm or insufficient melatonin secretion.3 Melatonin possesses hypnotic properties and it may simply be acting
in such a manner for FMS or CFS patients who are likely to have a sleep
disorder or problems falling asleep.
"The AFSA funding provided
data that assisted me with the renewal of our team's NIH-funded grant
to further examine the neuroendocrine biology in patients with FMS.
The melatonin study allowed us to exclude circadian phase shift as the
cause of the neuroendocrine alterations, which is very important to
our understanding of this perplexing condition. We have now completed
a detailed analysis of the pulsatile secretion of two components of
the stress axis, ACTH and cortisol. Furthermore, we have completed a
study of the responsiveness and resiliency of the HPA stress system.
It appears that the stress response defects in FMS patients are at the
level of resiliency (that is, how rapidly the HPA axis re-sets itself
after activation). We are continuing to try to understand why this is
the case and how these problems may be corrected therapeutically.
"Understanding the biology
of FMS patients helps in several ways. New knowledge that demonstrates
biological causes of FMS symptoms assists patients and their physicians
to more fully understand FMS. We have also used our research program
to train young investigators in Rheumatology, Neurology, and Cognitive
"I hope your donors
will recognize that their contributions have allowed investigators to
make incredible progress. In the last two years, three large pharmaceutical
companies have performed multicenter randomized controlled clinical
trial in patients with FMS a major milestone. We are now working
with the FDA to determine what kinds of studies would be needed for
a product to have a specific indication for the treatment of FMS (not
yet accomplished) that should encourage development of new and effective
treatments. It is my belief that the next five years will bring treatments
that will spur an educational effort directed towards primary care physicians
enabling more rapid diagnosis and treatment. I am very excited about
the opportunities this creates for improving the quality of life for
FMS patients. AFSA should be very proud of its funding accomplishments
over the past nine years!"
Autonomic Function in FMS and CFS
The autonomic nervous system
(ANS) is another one of the body's neuroendocrine systems that interacts
with the hypothalamus as well as the adrenal glandstwo ways in
which its function is linked to that of the HPA axis. Due to the interconnection
between the ANS and the HPA axis, both play a role in the body's stress
response mechanisms. Stress, when used to explain the actions of these
systems, takes on a broader meaning that goes beyond what people think
of as mental stress or worrying. Any type of challenge to the body is
considered a stressor, such as an infectious agent, exercise, physical
trauma, noxious odors/chemicals, or the mere stress of changing posture
from sitting to standing.
How your body responds to
a given challenge may alter your heart rate, breathing, digestive process
and many other systems. Fortunately, you don't have to consciously think
about these changes because your ANS automatically takes control of
the needed modifications. Catecholamines, such as epinephrine and norepinephrine,
play an important role in controlling the function of the ANS (they
are also commonly called adrenaline and noradrenaline (NA), the terms
used in Dr. Jasmin's work). The point is, increases or decreases in
these two neuro-hormonal substances may reflect the activation of the
ANS, and they have been the subject of much research in the field of
FMS. Not only does NA play a role in helping to regulate the body's
stress response mechanisms, but NA is also an important neurotransmitter
in the pain-inhibitory system (see the AFSA-funded studies performed
by Drs. Staud and Marchand).
In 1995, when Dr. Clauw was
funded by AFSA, no previous researcher had looked at the ANS function
in terms of NA levels in the blood or measured the balance between the
two branches of the ANS: the sympathetic and the parasympathetic. The
symptom of lightheadedness corresponding to a rapid drop in blood pressure
during tilt-table testing had been documented to occur in a subgroup
of teenagers with CFS, but the mechanisms by which this and other "dysautonomia"
type symptoms occurred was far from understood. So Clauw used the AFSA
award to better understand the tilt-table phenomenon. He also used Holter
monitors, which are portable 24-hour EKG measuring devices, to look
at the neuro-transmission of the heart and he measured the blood levels
of neuropeptide Y. This latter substance is a long-acting, more stable
form of noradrenaline.
The results of Clauw's AFSA
project were presented at the 1996 ACR meeting. To date, many researchers
have made similar observations that the ANS is not functioning properly
in people with FMS and CFS. In addition, the ability of various stressors
to activate the ANS in patients was the subject of research presented
at the 2002 ACR meeting by Clauw. He found that the levels of the catecholamines
(epinephrine and NA) were higher than the healthy controls for all test
periods in the study. When FMS and CFS patients were subjected to intense
physical exercise, the normal rise in catecholamine levels was significantly
less in patients who met the CFS criteria (with or without meeting the
tender point criteria for FMS). Clauw also showed that decreased heart
rate variability (HRV) exists in patients with FMS, CFS and Gulf War
Illness (GWI), but that this marker for dysautonomia is mostly found
in women, not men. Could this be a gender phenomenon? It's possible
and emphasizes the importance of taking gender into consideration when
analyzing research data.
So, what role do neuroendocrine
findings play in the symptoms, as well as the cause of, FMS and CFS?
Clauw says, "It is more likely that the abnormalities in HPA and
autonomic function are predisposing factors. Or, they could be due to
the illness itself (e.g., from problems of deconditioning or chronic
pain) rather than the cause of the symptoms."
Clauw was the first investigator
funded by AFSA, and at that time, funds from the government were very
limited for studying FMS/CFS. Reflecting back on his AFSA award, Clauw
provided the following answers to various questions:
did your award mean to you?
It was the first funding I ever received specifically for studying fibromyalgia.
did it enable you to accomplish?
It allowed our group to collect pilot data that served as the basis
for several successful Department of Defense (DoD) grant applications. (Why the DoD? Clauw was one of the first researchers to recognize
the strong overlap between FMS and GWI, and this allowed him to advance
the science of both conditions!)
What do you consider the greatest area of
benefit from your work?
Although the AFSA grant has not led to specific improvements in patient
care, it certainly led to a better understanding of how the autonomic
nervous system functions in patients with FMS.
new avenues of research resulted from your AFSA award?
Our group now has considerable federal funding to study FMS and other
related conditions, and the AFSA grant was critical in allowing us to
collect the pilot data that served as the basis for many of those applications.
Chemical sensitivities or
intolerance to odors, medications, foods and other substances are common
symptoms for most FMS patients. Iris Bell, M.D., Ph.D., of the
University of Arizona in Tucson, was awarded by AFSA in 1999 to look
at the mechanisms by which toxins may be causing an activation of the
CNS, which in turn, could exacerbate the symptoms of FMS/CFS. Bell evaluated
three groups: (1) FMS patients with chemical intolerance, or CI, (2)
FMS patients without CI, and (3) healthy individuals. Bell's previous
research shows that CI is a marker for heightened neural sensitization
and hypothesized that this could be occurring in patients with FMS,
especially with their elevated spinal fluid levels of SP and NGF.
What is neural sensitization?
Bell describes this as the progressive amplification of a given response
when repeatedly exposed to the same chemical stimulus. In the AFSA-funded
project, participants were exposed to a concentrated sucrose (sugar)
syrup three times, roughly one week apart. Then one week later, subjects
were given a placebo (pure water). They were also evaluated at baseline,
before they ingested the sucrose. Each study participant underwent blood
tests and filled out questionnaires to assess diet, symptoms, sugar
cravings, mood, and other factors during the two weeks preceding the
baseline evaluation. Before, during and after the sucrose administration,
Bell measured each person's brain electrical activity using a computerized
electroencephalogram (EEG). An EEG measures brain wave frequencies through
the placement of electrodes on the scalp at 16 specified locations.
Each location correlates with brain structures.
Bell observed several abnormalities
in FMS patients that seemed accentuated by the presence of CI, and she
published two reports on the study.4,5 FMS patients had substantially
lower resting blood sugar levels and higher carbohydrate cravings than
the controls. When exposed repeatedly to sucrose, patients also exhibited
increased alpha wave activity in the front midline areas of the cortex,
as measured by EEG. Alpha waves slow down the function of the brain,
interfering with cognition and other CNS processes. Based on her AFSA
project, Bell received an NIH grant to look at the impact of diet, biofeedback
and odor (aromatherapy) on FMS symptoms, EEG, and ANS function (e.g.,
heart rate variability).
- Korszun A, et al. Melatonin Levels in Women with FMS and CFS. J Rheumatology 26(12):2675-80, 1999.
- Klerman EB, et al. Circadiam Rhythms Of Women with FMS. J Clin Endocrinology Metabolism 86:1034-39, 2001.
- Citera G, et al. The Effect of Melatonin in Patients with FMS: A Pilot Study. Clin Rheumatology 19(1):9-13, 2000.
- Bell IR, et al. Concomitant Environmental CI Modifies the Neurobehavioral Presentation of Women with FMS. JCFS 9(1/2):3-19, 2001.
- Bell IR, et al. EEG Beta 1 Oscillation and Sucrose Sensitization in FMS with CI. Intern J Neuroscience 108:31-43, 2001.
[Back to Table of Contents]
Brain Imaging Studies
AFSA has funded four studies
involving the use of brain imaging techniques. Two projects were awarded
to Laurence Bradley, Ph.D., of University of Alabama at Birmingham
(UAB). Bradley used SPECT (single-photon-emission computed tomography)
in combination with MRI to analyze blood flow to various regions in
the brain. The SPECT scanner detects the blood flow while the MRI allows
Bradley to accurately identify the location in the brain where abnormalities
in blood flow are detected. Muhammad Yunus, M.D., of the University
of Illinois College of Medicine in Peoria, used a different imaging
technique, called PET (positron emission tomography) in an effort to
try to pinpoint the location of brain dysfunction and potentially the
neurotransmitters involved (see Web site for details). The forth study
was awarded to Patrick Wood, M.D., at LSU in Shreveport, to use
yet a different technique called proton MRS, and this happens to be
the most recent project funded by AFSA.
Each imaging study was designed
to provide different insights into the brain malfunction of patients
with FMS. AFSA and its funded investigators have held strongly to the
belief that FMS (as well as CFS) is linked to serious abnormalities
in brain function. Identifying these defects as well as showing that
they are not caused by depression or mood states is a challenge. Fortunately,
experience and improvements in brain imaging techniques are proving
to be beneficial to researchers in this field. An update on the brain
imaging findings funded by AFSA is provided below.
Pain Sensitivity Real ... and made worse by anxiety
It may just appear that
FMS patients are hypersensitive to pain, but Bradley confirmed the enhanced
pain perception in patients. He used random, blinded testing of pressure
stimuli and found that the pain threshold of FMS patients is roughly
one-half of the value for healthy pain-free controls. Low pain thresholds
are real! He also discovered that when individuals with FMS were exposed
to a random set of either painful or nonpainful stimuli, the brain blood
flow (as measured objectively by SPECT scans) indicated that the brains
of patients responded differently from those of healthy controls. What
does this mean? Regardless of whether the stimulus was above their pain
threshold, the anxiety and anticipation of being prodded generated significant
increases in blood flow to certain limbic centers in the brain, particularly
those involved in pain control. The impact of being subjected to pressure
stimuli was the greatest for patients who already suffered from pain-related
This project was presented
at the 2000 American College of Rheumatology meeting as well as the
April 2001 American Pain Society meeting. An abstract of the preliminary
findings are posted on AFSA's Web site at: www.afsafund.org. Although
therapies that may reduce anxieties might help, Bradley is continuing
in his efforts to identify the physiological mechanism responsible for
this enhanced brain blood flow generated by the anticipation of pain.
At the October 2002 American
College of Rheumatology meeting, Bradley presented data showing that
resting levels of blood pressure or heart rate (two variables that might
be tied to one's stress level) did not correspond to the degree of blood
flow changes. Bradley is looking to evaluate other neuroendocrine factors
that may be tied to the altered blood flow changes caused by anticipation
of a painful stimulus. The bottom line, however, is that pinpointing
the mechanisms involved will likely lead to better therapies for FMS
symptoms, and not just the pain. The limbic regions that Bradley evaluated
are involved in regulating sleep and aiding with cognition.
FMS Not Depression!
The award enabled doctoral
student Leanne Cianfrini, M.A., to work with Bradley to complete
a study in which she compared the pain responses of women with either
FMS or major depressive disorder to those of healthy individuals. The
pain responses included (a) pressure pain threshold levels and (b) changes
in brain blood flow elicited by a 4-minute period of pressure stimulation
that was tailored so that each individual would experience similar pain
intensity levels. Cianfrini found that the patients with FMS produced
pain responses that were substantially different from those of the patients
with depression and the healthy persons. However, the depressed patients'
responses were not different from those of the healthy persons. These
results, which will soon be submitted for evaluation by a medical journal,
strongly suggest that depressive illness alone does not alter pressure
pain sensitivity or brain blood flow responses to painful pressure stimulation.
Cianfrini and Bradley believe
that communicating these and similar findings to health care professionals
and to patients with FMS will help reduce the extent to which the painful
symptoms of FMS are inappropriately attributed solely to depression
or other psychiatric disorders.
Cianfrini will soon complete
her Ph.D. and continue her research on FMS, beginning with her internship
training that started in 2003. To date, three AFSA awards have been
made to Bradley (in conjunction with one of his doctoral students).
Two of them were in the area of brain imaging, and the third one on
genetics will be described in the next section. When asked about the
AFSA grants, Bradley and Cianfrini provided the following comments to
help explain how your contributions are working to advance research
"It has been a great
pleasure to work with AFSA over the past eight years and we greatly
appreciate the opportunity to describe how patient donations to AFSA
have helped us further our understanding of FMS. Our colleagues at the
University of Alabama at Birmingham (UAB) include both clinical and
basic scientists in the Division of Clinical Immunology and Rheumatology,
the Department of Physiology and Biophysics, the Division of Neuro-Nuclear
Medicine, the Medical Genetics Laboratory, and the Department of Biostatistics.
We also collaborate with clinical and basic science colleagues at universities
in the United States, Canada, and in Europe. In addition, several graduate
students have completed their doctoral studies in our laboratory with
AFSA support. These new investigators include Leslie A. Aaron, Ph.D.,
MPH, who is continuing her research on FMS and CFS at the University
of Washington (working with Dedra Buckwald, M.D.), Kristin
R. Alberts, Ph.D., who is now at Jacksonville University in Florida,
and Ronald Alexander, Ph.D., who is a Major in the US Air Force.
"We have been awarded
three grants from AFSA. Two of these grants have allowed us to study
the extent to which depression and other mood states influence pain
sensitivity and brain function in patients with FMS and the third grant
allows us to produce renewable samples of DNA from consenting patients
and their family members for current and future studies of genetic influences
on pain sensitivity in women with FMS. These grants have contributed
to our ability to compete successfully for larger research awards from
the National Institutes of Health (NIH), which has supported our work
since 1992. In addition, AFSA grants have provided support for studies
of important FMS-related problems that could not have been examined
through NIH grant mechanisms. A good example was the study performed
by Cianfrini to demonstrate that FMS is not a form of depression.
"We hope this article
has increased your understanding of how the AFSA research grant program
has provided great help to our FMS research program and to the training
of new FMS investigators in our laboratory. It is important to remember,
however, that a large number of investigators have received research
support from AFSA. Thus, our experience is just one example of the very
positive influence of AFSA on FMS research across the United States.
We wish to thank AFSA for its support and especially thank everyone
in the FMS community for their contributions to the AFSA research grant
New Imaging Technique Shows Promise
The last study AFSA funded
in November of 2002 was in the area of brain imaging. Patrick Wood,
M.D., the study's principal investigator and an assistant professor
of medicine at LSU in Shreveport, LA, is in the process of evaluating
FMS patients using proton MRS technology. The MRS stands for magnetic
resonance spectroscopy. As described in our last Update, this brain
imaging tool allows scientists to measure the chemical content of various
tissues within the brain, and this in turn can help explain why the
brain is not functioning properly in people with FMS.
Wood is already underway
with his study and is focusing his attention on the hippocampus region
of the brain. This is an area within the limbic system that plays a
role in memory and learning, stress inhibition, and the routing of pain
signals from the spinal cord to the brain. The hippocampus communicates
with several other important structures as well, such as the hypothalamus,
locus coeruleus and the amygdala. So if the structural integrity of
the hippocampus is disrupted in patients with FMS, this could explain
many of the symptoms and drugs known to protect the hippocampus may
The description of Dr. Wood's
study which appeared in the November 2002 Update, prompted a number
of questions about how this study might lead to treatments for FMS and
possibly CFS. Understandably, patients wanted to know what these "hippocampal
protective" drugs were and they wondered why we didn't list them.
The problem is that there are a variety of drugs that may protect the
hippocampus, but this is not the purpose for which these drugs were
designed and they may operate by a variety of different mechanisms.
With this in mind, we asked Dr. Wood questions pertaining to treatment
rationales based on his theory that the hippocampus' integrity could
be disrupted. Our questions and Wood's responses are provided for you
below so that contributors may better understand the importance of this
most recently funded project by AFSA.
Isn't the main goal of your project to provide baseline data on patients
so that you (or other investigators) can then proceed with drug testing?
First of all, if we can demonstrate a difference between
FMS subjects and controls with regards to the metabolite concentrations
within the hippocampus, then we have theoretical justification for treating
FMS patients (or, designing trials) with agents aimed at improving hippocampal
function and integrity. Second, the metabolites we are measuring via
MRS (especially N-acetylaspartate) are markers of neuronal function
and integrity. If we can indeed prove that there is a difference in
hippocampal function between FMS subjects and controls, and if (as suggested
by the medical literature) the hippocampus can be positively impacted
pharmacologically, then one would anticipate that these values in FMS
The research paper you sent AFSA regarding the role of estrogen replacement
therapy (ERT) implies that estrogen has a protective effect on the hippocampus.
Doesn't this impact your study design?
Yes, there is evidence in the literature to support the role of ERT
in maintaining hippocampal integrity as demonstrated by MRS. In order
to ensure that low-estrogen levels in our study participants do not
confound our findings, all study participants must be female and between
the ages of 30 50 with regular menstrual cycles. (This does
not mean that the data generated will not benefit men with FMS or women
who are post-menopausal; the rationale for testing only premenopausal
females was to minimize variability in our findings, especially since
this is a small, preliminary study.)
You have indicated that you use drugs to decrease glutamatergic hyperactivity
in order to decrease NMDA receptor activation. How do you decrease glutamatergic
activity with GABA-acting agents? In other words, how does this protect
It is helpful to think of many neurotransmitter systems as embodying
a sort of yin-yang balance between elements. Glutamate, which binds
to NMDA receptors, is the primary excitatory amino acid (the yin element
of neurotransmission). GABA, then, is the inhibitory yang, which balances
glutamate's excitatory influence. Excessive glutamatergic flow leads
to excitatory overload by allowing toxic levels of positive ions (such
as calcium) into the neuron. GABA-acting drugs allow the influx of negative
ions (such as chloride) into the neuron, to offset glutamatergic excitation.
On your long list of potential therapies for FMS, you have beta-adrenergic
receptor antagonism (lipophilic) drugs, and included in this category
is the drug pindolol. This is the drug that you tested in a preliminary
study involving FMS patients. Could you elaborate on why this class
of drugs might work and why you selected this drug to test? Also, don't
these drugs reduce blood pressure? Most patients with FMS have problems
with low blood pressure and any drug that even slightly reduces blood
pressure is not tolerated. Perhaps you could offer your theory on this
class of medications, and a brief description of them in layman's terms?
Yes! The rational behind the use of lipophilic beta-antagonists goes
something like this:
- FMS is a stress-related
condition; ergo, stress-related hormones (cortisol, CRH, norepinephrine)
must participate in FMS phenomena. (Stress
indeed, all of life
- Stress-related hormones
enhance NMDA receptor activity, including norepinephrine acting at
beta-adrenergic receptors within the hippocampus.
- NMDA receptors participate
in FMS phenomena, especially pain (per Arendt-Nielsen et al., and
- Ergo, block the cycle
of beta-adrenergic receptor/NMDA receptor synergy and you interfere
with the phenomena in which this interaction participates, including
(theoretically) stress-related pain transmission. Voila!
It is therefore also intriguing
to note that propranolol, another lipophilic beta-antagonist is already
used in the prophylaxis of migraine headaches, another pain disorder
related in part to NMDA receptor dysfunction.
As far as the low blood pressure
is concerned, the reason for this (I believe) may be derived from the
work which has demonstrated excessive sympathetic activity in the context
of FMS. By analogy: it was once considered anathema to give patients
with congestive heart failure a beta-blockerthe rational being
that they needed sympathetic tone in order to compensate for their failing
hearts. As it turns out, the reason the heart is failing is that it
has withstood years of sympathetic hyper-drive, which has taken its
toll. It's now the standard of care to gently beta-block the patient
with congestive heart failure, in order to allow the failing heart to
recover sensitivity to adrenergic tone. Likewise, if we gently block
adrenergic (and noradrenergic) tone in FMS patients, who have withstood
years of adrenergic (i.e., sympathetic) hyper-drive, then we allow both
their neurological (hippocampal) systems, as well as their cardiovascular
systems (especially their baroreceptors that work to control blood pressure)
to recover normal function.
Pro-inflammatory cytokines have been described in the literature as
causing destruction of the hippocampus (apoptosis). There is a new drug
under investigation called CNI-1493. It is supposed to cross the blood-brain
barrier (very important) and acts like giving Valium to the activated
glial cells that are pumping out these awful cytokines. What are your
thoughts on these types of drugs that will soon be released for use
for other conditions (rheumatoid arthritis and Crohn's disease)?
I am interested in the cytokine inhibitors, although
I'm not sure to what extent cytokines play a role in the theoretical
disruption of hippocampal function and integrity in FMS. Two things
are noteworthy, though: IL-1b, IL-6 and TNF all participate in a feed-forward
cycle in conjunction with the stress hormone, CRH, in terms of revving
up the stress response. Therefore, it stands to reason that they may
play a role in the etiology of stress-related disorders of all stripes.
Secondly, elevated levels of circulating inflammatory cytokines (especially
IL-6) have been demonstrated in patients with congestive heart failure,
which have then been demonstrated to normalize following treatment with
carvedilol, a lipophilic beta-antagonist used to treat congestive heart
failure. (Things that make you go hmm
Is there anything you wish to add that would explain your concept of
protcting hippocampal function? Also, could you provide a short description
of what the hippocampus does?
The hippocampus is exquisitely sensitive to the effects of stress-related
hormones, which all act (by way of various mechanism) to enhance NMDA
receptor function and therefore excitatory signal flow. Excessive excitation
leads to atrophy and dysfunction. Therefore, anything which interrupts
the cycle of stress-related excitation has the potential to be beneficial
in the context of FMS.
So, what does the hippocampus do? Consider:
- The hippocampus is fundamental
to declarative memory. Hippocampal dysfunction would therefore lead
to slowing of information processing, degradation of short-term memory,
and errors in simple language processes (i.e., word-searching). This
might serve to explain the phenomenon of fibro fog.
- The hippocampus provides
the major inhibitory drive to stress response centers, including the
central amygdala and paraventricular nucleus, as well as the locus
coeruleus. Hippocampal dysfunction would then lead to an uninhibited
stress response system characterized by (1) excessive CRHergic activity,
and (2) sympathetic over-activity. In fact, both have been demonstrated
independently in the context of FMS.
- The hippocampus is a center
for pain signal processing, including chronic pain. The process of
hippocampal nociception is an NMDA receptor-related activity. It is
therefore especially intriguing that FMS pain has been demonstrated
to be a NMDA receptor-mediated process (at least in part) in a majority
[Back to Table of Contents]
What's Driving Your Symptoms
Speaking at the March 2003
American Pain Society meeting, Laurence Bradley, Ph.D., of the
University of Alabama at Birmingham (UAB), provided an overview on FMS.
He has evaluated pain thresholds from FMS patients in the community
as well as those who attend his UAB clinic for care. "Whether we
look at people from the clinic or from the community, we see widespread
abnormal pain sensitivity," says Bradley. "Essentially, the
pain thresholds for FMS patients are about one-half the level of the
measured values for healthy controls." Bradley went on to explain
that this pain sensitivity phenomenon was observed for both pressure
pain stimuli and thermal pain stimuli. Also, the finding that patients
have one-half of the pain threshold has been replicated by other laboratories,
including the University of Michigan team involving researchers Daniel
Clauw, M.D., and Richard Gracely, Ph.D.
The extensive pain sensitivity
and scientific data on FMS strongly point to the likelihood that FMS
is caused by abnormalities in the central nervous system's pain-processing
systems. The term for this in the pain literature is central sensitization,
but there is just one problem alluded to by Bradley. "If we are
going to assume that central sensitization might underlie the abnormal
pain sensitivity in FMS, we have to ask the question: What drives the
central sensitization?" He adds, "One of the investigators
who has really focused most of his attention on this problem is Haiko
Sprott, M.D., from Zurich, Switzerland." The question of what
is driving the central pain state involves looking at the tissues and
the blood for abnormalities that could be sending a steady stream of
nociceptive inputs (noxious signal transmissions) to the central nervous
Conceptually, a central pain
state cannot thrive by itself without noxious inputs to keep it going.
In this section, we describe research projects funded by AFSA that have
identified abnormalities in the periphery (tissues or blood) that could
be feeding the central pain state. In a manner of speaking, these factors
might be involved in driving your symptoms!
Abnormalities in the Skin
In 1997 and 1998, Haiko
Sprott, M.D., presented data on various abnormalities in the tissues
of patients with FMS that were all extremely intriguing. This was around
the time when most scientists were abandoning their search for abnormalities
in the tissues to hone in on problems in the central nervous system.
Sprott's initial work was not funded by AFSA, but caught the attention
of our grant reviewers. For example, he also found abnormalities with
the opioid receptor system in the skin of patients with FMS. The number
of patients tested was small and the results needed to be confirmed
on a larger scale.
In 1999, AFSA funded Sprott
to expand his work on evaluating the opioid receptors in the skin of
patients with FMS. His preliminary findings were described in our August
2001 Update. There are three types of opioid receptors: mu, delta and
kappa. Sprott found that the kappa and the delta opioid receptors were
increased in the skin of people with FMS, with the finding being most
significant for the delta receptor. Despite the increased population
of opioid receptors, patients with FMS still have significant levels
of pain. Medications that work on the delta opioid receptor may open
up a new avenue of treatments for FMS, possibly with fewer side effects
because they would act on the receptors in the periphery rather than
those in the central nervous system.
Sprott plans to continue
his work in this area to investigate why these opioid receptors are
increased in the skin of patients with FMS. Further experiments will
also be needed to convince the pharmaceutical industry to create specific
drugs that could target the opioid receptor anomaly found in FMS.
Recently, Sprott and coworkers
published findings of elevated cytokines in the skin of people with
FMS.1 Roughly 30% had increased concentrations of interleukin-1b
(IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a)
... all pro-inflammatory cytokines. He hypothesizes that a subset of
FMS patients are experiencing an inflammatory-like phenomenon in their
tissues and that this may be why some patients respond to anti-inflammatory
medicines (e.g., ibuprofen, naproxen, etc.). The possible link between
the abnormality in opioid receptors and the presence of cytokines in
the skin of a subset of FMS patients is an area of future research that
Sprott is interested in exploring.
Sprott is a rheumatologist
at the Center of Experimental Rheumatology and WHO (World Health Organization)
Collaborating Center for Molecular Biology and Novel Therapeutic Strategies
for Rheumatic Diseases. He is in the process of preparing manuscripts
on his AFSA-related findings and has kindly provided feedback for our
donors about the significance of his two AFSA awards:
- The two awards gave me
the opportunity to investigate possible new pain mechanisms in FMS
patients. This in turn will hopefully provide input to the pharmaceutical
industry to develop and/or to check specific drugs for FMS patients.
- With AFSA's assistance,
we were able to step into a new field in FMS research, in particular,
to investigate novel pain mechanisms in this disease.
- Although our research
is basic science in nature, we hope to identify the pain regulatory
mechanisms involved in FMS. Such input will help us learn more about
how the symptoms are generated and might help to develop new strategies
in pain management for this patient group.
- As our next step, it will
be important to further analyze these preliminary results, confirm
them, and then determine if they are specific for FMS, or if they
might also be present in other painful diseases.
Cytokines in the Blood
Traditionally, cytokines are considered in connection with autoimmune
and inflammatory disease, such as rheumatoid arthritis, lupus, and Crohn's
disease. Elevated cytokines are thought to be markers of immunological
diseases, or that was the prevailing theory. However, in the 1990s,
a few research teams reported on various immunological abnormalities
in patients with FMS, including Daniel Wallace, M.D., professor
at UCLA and rheumatology researcher in Los Angeles. In 1999, Wallace
proposed to AFSA that various pro-inflammatory cytokines be looked at
in connection with FMS.
At the same time, Linda
Watkins, Ph.D., of the University of Colorado in Boulder, was conducting
studies to show that elevated pro-inflammatory cytokines could lead
to pathological pain states ... and possibly FMS. Recently, Watkins
published a medical report explaining how cytokines are produced by
the immune system's glial cells that reside in the spinal cord.2 They also serve as the communicating link between the immune system
and the central nervous system. When the glial cells become activated,
for whatever reason, they produce pro-inflammatory cytokines. However,
it can be hard to measure them because their concentration becomes diluted
when they enter the general blood pool. In healthy humans, these glial
cells are not activated, and therefore, don't produce pro-inflammatory
What causes the glial cells
to become activated? Watkins has been able to identify many neurochemicals
capable of triggering their activation, such at NGF, SP, and NO. All
of these substances are elevated in the spinal fluid of patients with
Understanding of the so-called
neuro-immune link was in the early stages when Wallace submitted his
proposal to AFSA. In fact, much still remains unclear. Fortunately,
Wallace's findings have opened the eyes of many scientists in the field.3 Who would have thought that FMS had an immunological component and that
these same substances (IL-1, IL-6, and IL-8) may be operating in the
peripheral blood to feed or drive the central pain state? Wallace did
back in 1999, and he has proven his "hypothesis" with excellent
data generated by an AFSA-funded project. His findings were published
in the July 2001 issue of Rheumatology and described in the January
2002 AFSA Update (now posted to our Web site). In addition, other investigators,
such as Sprott, as well as Ali Gur, M.D., of Turkey, have also
confirmed that cytokines are involved in FMS. It is unclear if they
are the cause of FMS symptoms or are they the result of other problems
going on in the central nervous system. However, Gur's findings have
shown that the abnormalities in cytokines are associated with altered
blood flow measured by SPECT analysis and that the elevation in IL-8
is strongly linked to pain intensity.4,5
Why not shut down these nasty
cytokine chemicals? Early drug development generated medicines that
targeted only one cytokine, and they have to be injected either daily
are bi-weekly (Kineret and Enbrel). These two drugs were made with rheumatoid
arthritis in mind and probably do an okay job, but they won't help FMS
patients. Not only do they target a single cytokine (IL-1 and TNF-a,
respectively), they don't cross the blood-brain barrier. This oversight
may not be devastating to patients with peripheral joint inflammation,
such as RA, but it dramatically cripples the use of these drugs for
central pathological pain states, such as FMS.
A new class of drugs, called
MAP Kinase Inhibitors, are now entering the early stages of human trials
for RA and Crohn's disease, and according to Watkins, they work to reduce
the production of all pro-inflammatory cytokines from the glial cells.
In fact, she described them at the March 2003 "Focus on Pain"
conference as having a powerful calming effect on glial cells, greatly
reducing their production of pro-inflammatory cytokines. But, will this
new class of drugs cross the blood-brain barrier? Yes! Watkins was keen
to investigate this issue (at least in rodents) over two years ago and
published her results.6
Wallace's study was able
to document elevated cytokine production very early on in the development
of FMS, and this was confirmed by Gur. How early? Within the first two
years of the appearance of symptoms. So drugs that quiet down the glial
cells may provide an effective treatment option for patients with FMS,
and possibly CFS. Wallace and Watkins are both actively trying to convince
the manufacturers of MAP Kinase Inhibitors to consider testing their
novel drug on patients with FMS, as well as CFS.
With the aid and friendly
encouragement of Watkins, AFSA developed a "fact sheet" and
approached one pharmaceutical company to determine their interest in
having their newly developed drug tested in patients with FMS (the Fact
Sheet is reprinted on the last four pages of this Update). Like all
of the other companies, the one we approached has entered the early
stages of human clinical trials and their drug is not yet FDA approved,
but they are working on it. The good news is that they are willing to
collaborate with AFSA, provide their drug free-of-charge for research,
and complete the lengthy paperwork requirements with the FDA. However,
they are a smallyet open mindedcompany that can't afford
to pay for the trial itself. This means that AFSA must locate a qualified
researcher (preferably one who is well-published) to perform a preliminary
drug trial without a mega-buck stipend. AFSA's grant awards of $50,000
pale in comparison to what researchers are used to receiving from large
If you are a patient who
is under the care of a successful rheumatology researcher, please ask
them if they are interested in performing a pilot study using a MAP
Kinase Inhibitor. Many rheumatologists are familiar with these drugs
because they are being tested in patients with RA, and they are also
most likely to have the technology to assay for cytokines because these
evaluations are often performed by rheumatic disease investigators.
Give them a photocopy of AFSA's Fact Sheet and let him or her know that
they may contact us for more details. Unlike the rest of this Update,
which is copy-protected, we encourage you to photocopy the FMS Fact
Sheet for your physician ... even if they are not a researcher, they
may find it informative.
Natural Pain Fighters Under Attack?
We described the pain-relieving
system in the section on Tests To Validate Your Pain, and in that section,
we mentioned that the body produces natural pain fighters such as endogenous
opioids, endorphins, and enkephalins. According to Thomas Fasy, M.D.,
Ph.D., at Mount Sinai School of Medicine in New York City, there
are more than 20 different compounds that would fall into the category
of natural pain relievers called opioid peptides, including a recently
identified compound called nocistatin. Nocistatin is made up of amino
acids (that is why it is called a peptide) and has been shown to relieve
pain. The site at which nocistatin works is within the spinal cord neurons,
where the incoming neurons connect with the spinal neurons that relay
messages to the higher centers in the central nervous system.
Fasy's first AFSA-funded
project awarded in the year 1999 hypothesized that possibly one or more
of these natural pain fighters might have autoantibodies that destroy
them. If patients with FMS did have autoantibodies attacking their natural
opioid peptides, this could explain the widespread pain, enhanced pain
perception, and possibly other symptoms that might result from problems
in pain-processing. In fact, the presence of autoantibodies could be
one of the forces driving the central pain state of FMS.
The two major goals of Fasy's
1999 award were: (1) screen strains of mice with autoimmune diseases
for the presence of autoantibodies to opioid peptides so that they could
be used for human analyses, and (2) test the blood sera of 20 FMS patients
and 20 matched healthy controls for the presence of autoantibodies.
Fasy found one particular mouse strain that produced many different
autoantibodies. He also estimated that one-third of the sera of patients
with FMS had autoantibodies to nocistatin. This finding in the sera
does not preclude the possibility that other autoantibodies acting on
the receptors in the spinal cord may even be more problematic in a greater
percentage of patients.
What can be done to compensate
for these autoantibodies against nocistatin? Fasy says that there are
two different types of drug therapies that may indirectly help the natural
opioid pain system work more effectively. Both are still in the developmental
stage but appear to be promising for FMS therapy. One class inhibits
the enzymes that normally breakdown the opioid peptides, so that these
pain relievers last longer. The other class acts on the enkephalin receptor
to mimic the action of the pain-fighting enkephalins. Interestingly,
this latter class of drugs operates on the delta opioid receptor. This
approach could tie in Sprott's work, which shows an increased concentration
of delta opioid receptors in the skin of FMS patients. Fasy adds that
studies in rodents indicate that drugs which specifically activate the
delta opioid receptor induce not only a pain-suppressing effect but
also a mood-elevating effect.
Laurence Bradley, Ph.D.,
provides yet another explanation of what may be driving your symptoms!
"Our most recent grant from AFSA has provided a very important
supplement to a new genetic-related project that is supported primarily
by the NIH. The major aim of this project is to examine sensitivity
to three forms of stimulation (pressure, heat, ischemic) among women
with FMS (i.e., probands), healthy control women, as well as the sisters,
brothers, and husbands of these women. This will allow us to determine
the extent to which the male and female relatives of the proband and
control women display abnormal pain sensitivity consistent with FMS.
While females are being selected to minimize genetic variability, both
male and female siblings which may also have FMS will be evaluated.
A second aim of the study is to determine the frequency with which a
specific structural defect or polymorphism occurs in the regulatory
region of the serotonin transporter gene among the participants in the
study. Two previous reports, one from Germany and the other from Israel,
have shown that this polymorphism is found more frequently in women
with FMS than in healthy women. However, we do not know to what extent
the polymorphism is found in the family members of these women. Due
to a limit on the budget we could propose to the NIH, we could not request
funds that would allow us to generate and store renewable samples of
genetic DNA from our consenting study participants. Thanks to support
from AFSA, however, we now have the funding to support this important
aim. This will allow us to identify the extent to which the family members
may differ with regard to the presence of this gene polymorphism as
well as other polymorphisms relevant to FMS that are identified in future
research. Thus, the support from AFSA will positively impact our current
and future research efforts. We hope that it increases the speed with
which investigators learn about genetic influences on the pain sensitivity
associated with FMS, thereby benefiting patients as well as their family
- Salemi S, et al. Detection of IL-1b, IL-6, and TNF-alpha in Skin of Patients with FMS. J Rheumatol 30(1):146-50, 2003.
- Watkins LR, Maier SF: Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82(4):981-1011, 2002.
- Wallace DJ, et al. Cytokines play an aetiopathogenetic role in FMS. Rheumatology 40:743-749, 2001.
- Gur A, et al. Regional cerebral blood flow and cytokines in young females with FMS. Clin Exp Rheumat 20:753-60, 2002.
- Gur A, et al. Cytokines and Depression in Cases with FMS. J Rheumatol 29(2):358-61, 2002.
- Milligan ED, et al. Systemic Administration of CNI-1493, a p38 MAP Kinase Inhibitor. J of Pain 2(6):326-333, 2001.
[Back to Table of Contents]
Investigating therapies that
appear promising but are not ordinarily prescribed for FMS/CFS patients
is a high priority for AFSA funding. This goal may seem straightforward,
but it is complicated by the multifaceted nature of the syndrome. Medications
that work for pain don't usually help with sleep. Those that help keep
patients alert and cognitively functional during the day don't mitigate
the pain or sleep problems, and in some cases, they might hinder sleep.
Then there are all of the other symptoms of FMS/CFS that often require
specific treatments (both drug and nondrug), such as headaches, irritable
bowel, jaw pain and dysfunction, and exercise intolerance. This means
that the gold standard of treatment trials, which dictates that one
group of patients be tested on a single medication while the other group
takes a placebo, can present many problems when studying FMS/CFS therapies.
Still, AFSA has funded four exceptional treatment trials on FMS/CFS
patients to help open the door to treatments that may be underutilized.
They also offer an understanding about why the prescribed therapies
might work better in some patients as opposed to others.
As Dr. Leslie Crofford states
in the "Neuroendocrine" section, the pharmaceutical industry
is finally looking into therapies for FMS/CFS. This major accomplishment
is essential for the future well-being of patients, but the drug company
trials will take time and they will not involve inexpensive, unpatented
medications that are currently available to patients. This is where
AFSA funding can play an essential role in researching treatments. Our
funding enables researchers to investigate drugs that are available
to patients now!
Many clinicians say that
when they add clonazepam to their patient's treatment regimen, they
find it very helpful. Although clonazepam is not under a patent (and
therefore is relatively cheap), it is a benzodiazepine. Benzodiazepines
are scheduled drugs, and because of this, physicians may avoid prescribing
clonazepam to their FMS/CFS patients. Given the reluctance of many physicians
to prescribe this readily available drug, Don L. Goldenberg, M.D.,
Professor of Medicine at Tufts University and Chief of Rheumatology
at Newton-Wellesley Hospital, was awarded a grant to look at the efficacy
of low-dose clonazepam in patients with FMS. Goldenberg, like many other
clinicians, had found this drug to be very safe and free of most adverse
side effects but its actual benefit to patients remained unknown. Does
it work to improve sleep? Does it reduce anxiety as many benzodiazepines
do? Does it impact pain in patients with FMS? These and many other questions
needed to be answered.
Below, Dr. Goldenberg summarizes
his study design (as illustrated in the diagram), his findings and their
significance for patients with FMS ... and most likely for patients
diagnosed with CFS:
"From January 21, 2000
until December 1, 2000, we enrolled 16 patients in a randomized trial
of clonazepam versus placebo in fibromyalgia. This was designed as a
crossover study and each patient received 0.5 mg of clonazepam and an
identical looking placeboeach for a 12-week period. There was
a washout period during which no medications were taken between the
two 12-week sessions. In this crossover design, each patient functioned
as their own control. The patients were examined at six points during
the study. We evaluated each patient's tender points as well as each
patient's assessment of global well-being, pain, sleep, and fatigue
at six different time intervals.
"For each of these parameters,
we found no significant difference in clonazepam versus the placebo.
Although clonazepam improved sleep and fatigue significantly, the placebo
response was just as robust. There was more of a homogeneity (consistency)
in the response to clonazepam, whereas the placebo response varied dramatically.
Some patients got much worse on placebo, but some surprisingly got much
"I do believe that clonazepam
is a useful medication for FMS despite these results. However, it is
not appropriate as a single medication since its primary effect is in
regard to the sleep disturbances. It probably works best in patients
who also have restless legs syndrome or periodic limb movements during
sleep, and we did not assess these conditions during the study because
it would have required expensive overnight sleep lab testing. We also
might have obtained better results if we had used a slightly higher
dose, such as 1.0 mg of clonazepam at bedtime. Finally, this randomized
clinical trial demonstrates the importance of doing medication studies
with a placebo and demonstrates the well-know, powerful effects that
a placebo can have in the short-term."
Goldenberg did not encounter
noticeable side effects with the use of clonazepam, nor did he observe
any habituation problems after the 12 weeks that patients were placed
on this drug. A simple one-week washout period was both safe and adequate.
This study was designed to test the efficacy of clonazepam alone, despite
the fact that most patients use multiple therapies for their many symptoms.
If you are having sleeping problems similar to restless legs or uncontrollable
limb movements, clonazepam may be a viable, safe option that may be
"added on" to your other therapies to improve your quality
of life. A reasonable starting dose is 0.5 mg, and based on Dr. Goldenberg's
comments, you and your doctor may consider increasing your dose to 1.0
mg before deciding whether this line of therapy is helpful.
Bromocriptine and Melatonin
The numerous hormonal (endocrine)
and neurotransmitter abnormalities in FMS patients present a treatment
challenge. Serotonin in the blood and central nervous system appears
to be low in FMS, and this could cause problems in the body's production
of many hormones. In turn, these hormones may have a diverse impact
on the symptoms of FMS, including pain and disturbed sleep. The breakdown
product of dopamine (homovanillic acid) is also reported to be low in
the spinal fluid of patients with FMS and represents yet another neurotransmitter
that has a diverse impact on the way the body's neuroendocrine system's
function.1 For example, low dopamine levels are associated
with higher than normal production of prolactin from the pituitary,
which is known to increase anxiety. It's also believed to be low in
patients with certain sleep disorders that are fairly common in FMS:
restless legs syndrome (RLS) and periodic limb movements during sleep
of serotonin and dopamine levels in patients with FMS should lead to
symptom improvements. This is what Robert McMurray, M.D., Chief
of Medicine at the VA Hospital in Jackson, MS, proposed in his application
to AFSA. McMurray evaluated the treatment of 16 patients in a double-blinded,
placebo-controlled study of two different therapies taken at night for
FMS: 6 mg of melatonin or 2.5 mg of bromocriptine. Melatonin works to
increase brain serotonin levels, and has hypnotic effects that may aid
sleep as well. Bromocriptine acts like dopamine and it also produces
an anti-anxiety/anti-stress effect. McMurray figured that both therapies
used together would work better than either one individually, but the
purpose of the study was to tease out the specific effects of melatonin
The cross-over design, as
illustrated in the diagram above, took 16 months for each participant
to complete. Patients spent four months on placebo, four months on melatonin,
four months on placebo, and then four months on bromocriptine. All patients
were analyzed every four months of the study for the number of tender
points, dolorimeter scores (estimate of pain tolerance), sleep, fatigue,
pain, and morning stiffness. In addition to symptom parameters, McMurray
also measured blood hormone levels of melatonin, prolactin, and cortisol.
Cortisol was measured to estimate each person's stress level (stress
activates the HPA-axis, which should then produce higher levels of cortisol).
According to McMurray, initial analysis of the data suggest that each
of the two medications may be useful for a subgroup of FMS patients.
On the whole, there was a
26% reduction of subjective pain in patients on bromocriptine compared
to placebo (preliminary assessment). Some patients had dramatic improvements,
however, that were hidden by statistical analysis, so McMurray looked
at individual responses in the 16 subjects. He also compared the hormonal
changes in patients who exhibited a positive response to determine if
there were any trends that could predict a response to either drug.
Six of sixteen patients (38%)
had a significant decrease in tender point number during treatment (4
with melatonin; 1 with bromocriptine; 1 with either drug) compared to
their respective placebo phases. The average reduction in the number
of tender points was 47% (14 tender points to 7.2 tender points) for
melatonin. Similarly, six of sixteen patients (38%) had an increase
in pain tolerance as measured by dolorimetry (2 with melatonin; 2 with
bromocriptine; 2 with either drug) compared to placebo phases. Pain
tolerance increased 68% in melatonin responders and 95% in bromocriptine
responders. Melatonin improved sleep an average of 56% for the three
patients responding to this drug. Neither drug produced any changes
in fatigue or morning stiffness values. On average, it took close to
three months to achieve the maximum benefits from either drug, and only
one patient was identified as a "placebo responder."
here to see a table summarizing McMurray's results (PDF)
Overall, there were no differences
in serum hormone concentrations of melatonin and prolactin during any
of the phases. However, in patients responding to either drug, serum
melatonin concentrations during treatment doubled. From this preliminary
data, it appears that when either melatonin or bromocriptine produces
a positive effect in FMS patients, it corresponds with a dramatic increase
in their serum levels of melatonin (unpublished observation).
In contrast to the elevation
of melatonin, there were no significant differences in serum prolactin
concentrations between responders and nonresponders. This occurred despite
the administration of the bromocriptine, a known prolactin suppressive
drug. This suggests that either prolactin does not play a substantial
role in the pathogenesis of FMS or that a 2.5 mg dose of bromocriptine
was not sufficient to cause a reduction in prolactin levels and a higher
dose may have been more effective. Similarly, there was no significant
abnormality in serum cortisol concentrations or in the results of the
dexamethasone suppression tests (used to look at the production of cortisol
from the adrenal glands).
Preliminary analysis of study
participants revealed subsets of FMS patients (20-40%) responding to
neuroendocrine manipulation with either melatonin or bromocriptine,
characterized by a decrease in tender points, an increase in dolorimetry,
or sleep improvement. The average time to maximal response was approximately
three months for either drug and improvement was associated with increased
serum melatonin concentrations during the response period. McMurray
cautions that the above information is only a preliminary analysis of
his study and that formal publication of his data may provide more definitive
conclusions. Also, further studies will be required to elucidate the
significance of the above observations.
In an article published in
August of 2001, Dr. McMurray reviews the use of bromocriptine for treating
rheumatic and autoimmune diseases, including lupus, rheumatoid arthritis,
FMS, migraine headaches, premenstrual syndrome, and fatigue.2 He says that bromocriptine may be a nonstandard or add-on therapy for
these conditions when they are unresponsive to traditional approaches.
How does a drug that acts like dopamine work in these diseases that
have such different physiologic causes? McMurray indicates that bromocriptine
has many possible modes of action in addition to lowering prolactin
levels, such as suppressing cytokine production (especially IL-6) or
reducing nitric oxide. Elevated cytokines and nitric oxide production
have both been found in patients with FMS.
A newer drug that works like
bromocriptine, called Mirapex, was recently shown at the 2002 American
College of Rheumatology meeting to be helpful for a subset of FMS patients.
The purpose of the study (yet to be published), conducted by Andrew
Holman, M.D., of Renton, WA, was to show that by adding a small
dose of Mirapex onto the existing treatment regimen for 27 FMS patients,
that their painful symptoms would be significantly reduced.3 The trial
was not blinded or placebo-controlled, nor were any neuroendocrine measures
taken to determine how the drug was producing its benefits in those
patients who responded to the drug. However, the results indicate the
need to better understand how dopamine-like drugs might ease the symptoms
Dextromethorphan plus Ultram
Dextromethorphan is an NMDA
receptor antagonist. Based on studies by Roland Staud, M.D.,4,5 and others, there is strong objective evidence that the NMDA receptors
in the spinal cord and brain are amplifying the painful impulses in
FMS patients. Dextromethorphan has few side effects and is a common
ingredient in over-the-counter cough syrups. Ultram has already been
documented in the medical journals by I. Jon Russell, M.D., Ph.D.,
and Robert Bennett, M.D., as being effective in reducing the
pain in many patients with FMS.6
Robert Bennett, M.D.,
of Oregon Health Sciences University in Portland, was awarded a grant
in 1997 by AFSA to look at the ability of dextromethorphan to boost
the action of Ultram, thereby providing better pain relief than Ultram
by itself. At the 2000 American College of Rheumatology meeting, Bennett
and his co-investigator, Sharon Clark, Ph.D., FNP, presented
the preliminary results of their study. The preliminary ACR abstract
is posted on AFSA's Web site. The study is now complete and has been
submitted for publication in a peer-reviewed medical journal. It is
hoped that this report will become available to treating physicians
worldwide before the end of 2003 or early 2004.
What is the significance
of this project to you, a contributor to AFSA? To help you evaluate
the answer to this question, Dr. Bennett kindly answered a few questions
posed to him regarding his award and the value of this project:
did the AFSA award mean to you?
Receiving a research grant is always an ego booster to a researcher
as it means that my peers have reviewed the proposal and found it worthy
of support. Due to the competitiveness of research, the majority of
grant proposals do not get funded; this is a fact of life for all researchers.
This particular proposal was modest in its scope and had little chance
of being funded by larger agencies such as the NIH. Much drug research
in FMS is funded by pharmaceutical companies; however this is not available
for drugs such as dextromethorphan which are not patentable and as such
offer no financial incentives to industry. Furthermore funding by AFSA
enables one to have more freedom in study design, with none of the "strings
attached" to industry sponsored studies.
did the project enable you to accomplish?
The notion that NMDA inhibitors may benefit FMS patients has only been
shown previously in short term studies of intravenous ketamine. This
current study was able to demonstrate that the orally available NMDA
inhibitor, dextromethorphan, when added to a weak opioid (in this case
tramadol) was of benefit to a subset of FMS patients in terms of improved
will patients benefit from the study?
Hopefully the results of this study will encourage other physicians
to use therapeutic trials of dextromethorphan as a supplemental agent
for pain management in FMS.
new avenues of research have resulted from this AFSA award?
I do not consider that this study has opened up any major new avenues
of research, but rather pointed to the relevance of considering an "enrichment
design" in some FMS studies. (By "enrichment," Dr.
Bennett refers to looking at the benefits of adding a new therapy onto
a person's existing treatment regimen. This enables study participants
to stay on stable doses of their current therapies, while the affects
of a new add-on therapy are evaluated. When a condition being studied
generates a multitude of symptoms and the underlying physiology is complex,
such as it is with FMS, the "enrichment design" enables researchers
to look at the added effect of a single therapy based on its suspected
physiologic role. In this case, the dextromethorphan was hypothesized
to interact with the NMDA receptors in patients to reduce pain amplification,
and thus further reduce the overall sensation of pain.)
Effexor's Impact on Pain Inhibition
Effexor-ER is the brand
name for the drug venlafaxine. It works primarily to increase serotonin
in the central nervous system, but its secondary mode of action is to
increase noradrenaline as well. However, Effexor's ability to raise
noradrenaline is not as potent as its primary action to raise serotonin.
As you have already read in "Objective Tests To Validate Your Pain," Serge Marchand, Ph.D., received an AFSA award in 2000 to conduct
several different related projects. First, it was essential to determine
if the diffuse noxious inhibitory control system (DNIC) could be accurately
tested in humans to develop a database by which FMS and regional pain
patients could be compared. As it turns out, the DNIC system does not
appear to be operating well in patients with FMS (although it works
well in regional low back pain syndrome patients) ... the manuscript
for this study is being prepared for publication.
Naturally, if researchers
find that a pain control system is not functioning up to par in patients
with FMS, the next step ought to be to look at pharmacological agents
that might help the system work better. This is the aim of the second
part of Marchand's study: to test the effectiveness of Effexor-ER in
25 FMS patients during an eight-week crossover trial. Marchand measured
the ability of each patient's DNIC system before and at the conclusion
of the study so that he could learn more about how the drug might work.
In most drug trials, medications are judged as helpful in a patient
subgroup (mostly based on subjective measures), but "how"
the drug operates in the body is rarely investigated. In the AFSA-funded
trial on Effexor, Marchand hopes to shed more light on explaining "how"
a drug that increases serotonin (and norepinephrine to some extent)
may work to modify the function of an important pain-inhibitory system
in the body.
Studies that look beyond
the question of whether a given drug is helpful generate lots of data.
Marchand was a key presenter at the 2001 American Pain Society's session
on fibromyalgia treatments, where he briefly described preliminary findings
pertaining to a portion of patients in the Effexor trial. However, the
job of compiling the large amount of data that was generated by the
study has taken considerable time. As soon as the Effexor study appears
in the medical journals, we will provide you with more details of the
study findings, along with feedback from Marchand regarding his interpretation
of the project outcome.
- Russell IJ, Vaeroy H, Javors M, Nyberg F: Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis & Rheum 35(5):550-6, 1992.
- McMurray RW: Bromocriptine in rheumatic and autoimmune diseases. Seminars in Arthritis and Rheumatism 31(1):21-32, 2001.
- Holman AJ: Pramipexole for fibromyalgia: the first open label, multicenter experience. Arthritis & Rheumatism 46(9, suppl):S108, abs#189, 2002.
- Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD: Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. PAIN 91(1-2):165-175, 2001.
- Staud R, Robinson ME, Vierck CJ, Price DD: Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. PAIN 101:167-174, 2003.
- Russell IJ, Kamin M, Bennett RM, Schnitzer TJ, Green JA, Katz WA: Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatology 6(5):250-7, 2000.
[Back to Table of Contents]